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Laminin

glycoprotein with antigenic properties localized in the basement lamina

Laminins are a family of glycoproteins of the extracellular matrix found in every known species in the biological kingdom Animalia. The laminins are essential for the structure and function of animal tissues. Defects in the genes that encode for laminins can cause a variety of diseases. Furthermore, bacteria and fungi that cause animal diseases often have genomes that encode proteins that can bind to various laminins in the animal hosts.

Illustration of the laminin-111 complex depicting the domain organization.

As of the end of the year 2021, fifteen different laminin types have been identified in humans. In 2005 a new laminin nomenclature was introduced. In the old nomenclature, laminin trimers in humans were numbered in the order in which they were scientifically discovered. For example, the trimer with chain composition α5β2γ1 is now designated laminin-521 instead of its old designation as laminin-11 (the 11th laminin type discovered). Laminin-11 was discovered in mice in 1997.

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  • The normal microbial colonization of sites in the body's tissues by certain bacteria requires that the bacteria first bind to extracellular secreted constituents, cell-surface membranes, or cell matrixes. This study examines two interactions of a variety of bacteria with the cell matrix noncollagenous proteins fibronectin and laminin and with basement membrane (Type IV) collagen. Adherence of bacteria to matrix proteins coated on tissue culture wells was examined with the use of radiolabeled bacteria. Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus sanguis bound well to fibronectin, laminin, and Type IV collagen, whereas a variety of gram-negative organisms did not bind. The interaction of soluble laminin, fibronectin, and Type IV collagen with bacteria was monitored by nephelometry with the use of a platelet aggregometer. S. aureus aggregated in response to fibronectin, laminin, or Type IV collagen. In contrast, gram-negative organisms did not aggregate with these proteins. It appears that fibronectin, laminin, and Type IV collagen can bind and aggregate certain gram-positive bacteria, and this binding is dependent on the surface characteristics of the organism. These adhesion molecules may play a role in the normal colonization of sites by microorganisms and in invasion during infections.
  • Anti-laminin antibodies were sought for in the serum of workers exposed to mercury vapour (Hg, n = 58), lead (Pb, n = 38) or cadmium (Cd, n = 47). Thirty-one workers removed from Cd exposure for an average of eight years were also examined. Compared with control workers matched for age and socio-economic status, the prevalence of circulating anti-laminin antibodies was not increased in workers exposed to Hg (mean duration of exposure: 7.9 years and mean urinary excretion of Hg: 72 μg/g creatinine) nor in those exposed to Pb (mean duration of exposure: 10.6 years and mean Pb levels in blood: 535 μg/l). In contrast, anti-laminin antibodies were significantly more prevalent in Cd-exposed workers whose urinary Cd exceeded 20 μg/g creatinine. This observation was made in both currently exposed workers and in workers removed from Cd exposure (mean duration of exposure: 9.4 and 24.6 years and mean urinary Cd: 7.8 and 13.4 μg/g creatinine respectively). These autoantibodies were found in Cd workers with normal renal function as well as in those with increased proteinuria.
    • (1987). "Search for anti-laminin antibodies in the serum of workers exposed to cadmium, mercury vapour or lead". International Archives of Occupational and Environmental Health 59 (3): 303–309. DOI:10.1007/BF00377742.
  • The major glycoprotein component of animal cell basement membranes, laminin, is involved in a variety of cellular activities, including cell adhesion, differentiation, and mito- genesis, that are mediated by the interaction of laminin with specific cell-surfacereceptors. A laminin-binding protein with an apparent molecular mass of 68 to 72 kD was first char- acterized in mammalian tumor cells and considered as “the laminin receptor” (Liotta et al., 1986; Wewer et al., 1986). Severa1 putative cDNA clones encoding this protein have been isolated from mammals (Yow et al., 1988; Rao et al., 1989; Van den Ouweland et al., 1989; Grosso et al., 1991). A11 the clones contained an open reading frame coding for a highly conserved polypeptide with a calculated molecular mass of 33 kD. Independently, a cDNA encoding an identical polypeptide was isolated from mouse tumor cells (Makrides et al., 1988), but the expressed protein, named factor p40, was shown to be a component of the translation machinery (Auth and Brawerman, 1992). Recently, DNA-deduced amino acid sequences exhibiting homology with the previ- ously characterized 33-kD ”laminin receptor” were identified from hydra (Keppel and Schaller, 1991), Drosophila (M.B. Melnick, T.B. Chou, and N. Perrimon, accession No. M90422), and yeast (J. Miles and T.G. Formosa, accession No. M88277).
    • (1993). "An Arabidopsis cDNA Encoding a 33-Kilodalton Laminin Receptor Homolog". Plant Physiology 103 (1): 299–300. DOI:10.1104/pp.103.1.299.
  • Extracellular matrix protein laminin binds specifically to yeast forms of Paracoccidioides brasiliensis and enhances adhesion of the fungus to the surface of epithelial Madin-Darby canine kidney cells in vitro. Immunoblotting of fungal extracts showed that the gp43 glycoprotein is responsible for adhesion. This was confirmed by binding assays using purified gp43, with a Kd of 3.7 nM. The coating of P. brasiliensis yeast forms with laminin before injection into hamster testicles enhanced the fungus virulence, resulting in a faster and more severe granulomatous disease. These results indicate that interaction of fungi with extracellular matrix elements may constitute a basis for the evolution of fungal infection toward regional spreading and dissemination.
    • (1994). "Binding of Paracoccidioides brasiliensis to laminin through surface glycoprotein gp43 leads to enhancement of fungal pathogenesis". Infection and Immunity 62 (4): 1465–1469. DOI:10.1128/iai.62.4.1465-1469.1994.
  • Pseudomonas aeruginosa is a major human pathogen known to infect tissues that have been previously damaged in some way. In wounded human respiratory tissues, P. aeruginosa cells were found attached to exposed basement membranes following epithelial denudation, suggesting that the affinity for extracellular matrix proteins may account for the bacterium's opportunistic character. By using microtiter wells coated with different P. aeruginosa strains, we demonstrated that laminin binds to both colonizing bacterial strains, isolated from asymptomatic carriers, and strains isolated from infected patients. Binding of soluble laminin to piliated P. aeruginosa PAK and to the nonpiliated isogenic mutant PAK/p—was shown to be saturable. Binding of laminin to the piliated PAK strain was not different from binding to the nonpiliated PAK/p—strain but was significantly higher than binding to the avirulent, nonpiliated PAK-N1 rpoN mutant. By transmission electron microscopy, we localized the laminin-binding sites on a loose material in the outermost layer of the bacteria. Western immunoblotting results suggested that 57- and 59-kDa nonpilus adhesins from the microbial outer membranes account for the binding of P. aeruginosa to laminin. We speculate that bacterial affinity for laminin may be of biological significance in the pathogenesis of P. aeruginosa infection of injured tissues.
  • Retinal explants from embryonic or adult mice were placed on laminin or merosin substrates and the outgrowth of optic fibers was assayed under serum-free conditions. Both substrates strongly promoted outgrowth. A blocking antibody to the β1/β3 integrin subunits completely blocked laminin-dependent growth of embryonic optic fibers but had no detectable effect on adult fibers. Similarly, a blocking antibody against the main neurite-promoting region within the globular domain of the E8 fragment of laminin inhibited growth of embryonic fibers but had no effect on adult optic fibers. The β1 integrin subunit was identified immunohistochemically on both embryonic and adult fibers. These findings indicate that adult fibers have lost the β1 function which dominates laminin-dependent growth in embryonic fibers but express a receptor for laminin-dependent growth that is not detectable in embryonic fibers. These findings suggest that there are intrinsic differences between embryonic and adult optic fibers that may have implications for regenerative failure in the central nervous system of adult mammals.
    • (1997). "The Neurite-Promoting Effect of Laminin is Mediated by Different Mechanisms in Embryonic and Adult Regenerating Mouse Optic Axonsin Vitro". Developmental Biology 181 (1): 91–101. DOI:10.1006/dbio.1996.8438.
  • Adhesion of Aspergillus fumigatus, the causative agent of human aspergillosis, to the extracellular matrix protein laminin has been previously demonstrated. This study investigated the expression of laminin receptors during swelling of conidia, a step leading to germination and subsequent colonization of tissues. Scanning electron microscopy showed that the laminin binding sites were distributed over the external rodlet layer of resting conidia. During swelling, the characteristic rodlet layer progressively disintegrated and conidia surrounded by a smooth cell wall layer appeared. Flow cytometry using fluorescein isothiocyanate-conjugated laminin demonstrated that expression of laminin receptors at the surface of conidia was swelling dependent. Resting conidia expressed high levels of laminin receptors on their surface. A gradual decrease of laminin binding was then observed as swelling occurred, reaching a minimum for 4-h-swollen conidia. This correlated with a loss of adherence of swollen conidia to laminin immobilized on microtiter plates. Trypsin pretreatment of conidia reduced laminin binding. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and ligand blotting with laminin identified in a cell wall extract a major 72-kDa cell wall glycoprotein which binds laminin. Thus, one of the initial events in the host colonization may be the recognition of basement membrane laminin by this 72-kDa cell wall surface component.
    • (1997). "Expression and identification of a laminin-binding protein in Aspergillus fumigatus conidia". Infection and Immunity 65 (1): 9–15. DOI:10.1128/iai.65.1.9-15.1997.
  • Laminins, heterotrimers of α, β, and γ chains, are prominent constituents of basal laminae (BLs) throughout the body. Previous studies have shown that laminins affect both myogenesis and synaptogenesis in skeletal muscle. Here we have studied the distribution of the 10 known laminin chains in muscle and peripheral nerve, and assayed the ability of several heterotrimers to affect the outgrowth of motor axons. ... we show that motor axons respond in distinct ways to different laminin heterotrimers: they grow freely between laminin 1 (α1β1γ1) and laminin 2, fail to cross from laminin 4 to laminin 1, and stop upon contacting laminin 11. The ability of laminin 11 to serve as a stop signal for growing axons explains, in part, axonal behaviors observed at developing and regenerating synapses in vivo.
    • (1997). "Distribution and Function of Laminins in the Neuromuscular System of Developing, Adult, and Mutant Mice". Journal of Cell Biology 139 (6): 1507–1521. DOI:10.1083/jcb.139.6.1507.
  • We have previously demonstrated that Staphylococcus aureus, a highly invasive bacteria, presents a 52-kDa surface protein that mediates its binding to laminin. In order to better characterize this receptor, we excised this putative laminin receptor from two-dimensional (2-D) PAGE and used it as antigen for raising a mouse hyperimmune serum which was for screening an S. aureus expression library. A single clone of 0.3 kb was obtained, and its sequence revealed 100% homology with S. aureus α-enolase. Moreover, amino acid sequencing of the 52-kDa protein eluted from the 2-D gel indicated its molecular homology with α−enolase, an enzyme that presents a high evolutionary conservation among species. In parallel, monoclonal antibodies raised against the S. aureus 52-kDa band also recognized yeast α-enolase in western blot analysis. These monoclonal antibodies were also able to promote capture of iodine-labeled bacteria when adsorbed to a solid phase, and this capture was inhibited by the addition of excess rabbit muscle α-enolase. Finally, the cell surface localization of S. aureus α-enolase was further confirmed by flow cytometry. Hence, α-enolase might play a critical role in the pathogenesis of S. aureus by allowing its adherence to laminin-containing extracellular matrix.
    • (2004). "Identification of enolase as a laminin-binding protein on the surface of Staphylococcus aureus". Microbes and Infection 6 (6): 604–608. DOI:10.1016/j.micinf.2004.02.003.
  • Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin β2 which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin β2 function is the molecular basis of Pierson syndrome. While truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist.
    • (2010). "Mutations in the human laminin β2 (LAMB2) gene and the associated phenotypic spectruma". Human Mutation 31 (9): 992–1002. DOI:10.1002/humu.21304.
  • Laminins are large molecular weight glycoproteins constituted by the assembly of three disulfide-linked polypeptides, the α, β and γ chains. The human genome encodes 11 genetically distinct laminin chains. Structurally, laminin chains differ by the number, size and organization of a few constitutive domains, endowing the various members of the laminin family with common and unique important functions. In particular, laminins are indispensable building blocks for cellular networks physically bridging the intracellular and extracellular compartments and relaying signals critical for cellular behavior, and for extracellular polymers determining the architecture and the physiology of basement membranes.
  • Laminin-211 is a major constituent of the skeletal muscle basement membrane. It stabilizes skeletal muscle and influences signal transduction events from the myomatrix to the muscle cell. Mutations in the gene encoding the α2 chain of laminin-211 lead to congenital muscular dystrophy type 1A (MDC1A), a life-threatening disease characterized by severe hypotonia, progressive muscle weakness, and joint contractures. Common complications include severely impaired motor ability, respiratory failure, and feeding difficulties. Several adequate animal models for laminin-α2 chain deficiency exist and analyses of different MDC1A mouse models have led to a significant improvement in our understanding of MDC1A pathogenesis. Importantly, the animal models have been indispensable tools for the preclinical development of new therapeutic approaches for laminin-α2 chain deficiency, highlighting a number of important disease driving mechanisms that can be targeted by pharmacological approaches.
  • Laminins are composed of three polypeptide chains, designated as α, β, and γ. The C-terminal region of laminin heterotrimers, containing coiled-coil regions, short tails, and laminin globular (LG) domains, is necessary and sufficient for binding to integrins, which are the major laminin receptor class. Laminin recognition by integrins critically requires the α chain LG domains and a glutamic acid residue of the γ chain at the third position from the C-terminus. Furthermore, the C-terminal region of the β chain contains a short amino acid sequence that modulates laminin affinity for integrins. Thus, all three of the laminin chains act cooperatively to facilitate integrin binding. Mammals possess 5 α (α1–5), 3 β (β1–3), and 3 γ (γ1–3) chains, combinations of which give rise to 16 distinct laminin isoforms. Each isoform is expressed in a tissue-specific and developmental stage-specific manner, exerting its functions through binding of integrins.
  • ... We here postulate that basement membrane laminin is the key antigen in driving psoriasis, inducing a T cell-mediated autoimmune response. For laminin to be considered as the key autoantigen in psoriasis, it would be reasonable to expect the following to be demonstrable: (1) that autoantigens are present in psoriatic inflammation; (2) that basement membrane laminin is perturbed in involved and uninvolved skin, and that some of the pathological changes associated with psoriasis could be predicted as a sequel to this; (3) that disruption of the basement membrane is among the earliest events in the evolution of psoriatic lesions; (4) that as streptococcal pharyngitis is the most clearly defined event to trigger or exacerbate psoriasis, then a T cell-mediated autoimmune response to laminin should be anticipated as a potential sequelae to streptococcal pharyngitis; (5) that T cells in psoriasis can be shown to react to peptides with homology to laminin; (6) that HLACw6, as the most closely related gene associated with psoriasis and which is involved in antigen expression, should be preferentially expressed within lesional psoriasis towards the basement membrane, together with other proximal associated immune activity; and (7) that there is some association between antilaminin pemphigoid, a humorally mediated autoimmune disease to skin basement membrane laminin, and psoriasis.
    • (2016). "A Review on the Potential Role of Basement Membrane Laminin in the Pathogenesis of Psoriasis". Scandinavian Journal of Immunology 83 (1): 3–9. DOI:10.1111/sji.12384.
  • Integrins play an important role in cell adhesion by linking the cytoskeleton of cells to components in the extracellular matrix. In this capacity, integrins cooperate with different cell surface receptors, including growth factor receptors and G-protein coupled receptors, to regulate intracellular signaling pathways that control cell polarization, spreading, migration, survival, and gene expression. A distinct subfamily of molecules in the integrin family of adhesion receptors is formed by receptors that mediate cell adhesion to laminins, major components of the basement membrane that lie under clusters of cells or surround them, separating them from other cells and/or adjacent connective tissue. During the past decades, many studies have provided evidence for a role of laminin-binding integrins in tumorigenesis, and both tumor-promoting and suppressive activities have been identified.
  • Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) is a devastating neuromuscular disease caused by mutations in the LAMA2 gene. These mutations result in the complete absence or truncated expression of the laminin-α2 chain. The α2-chain is a major component of the laminin-211 and laminin-221 isoforms, the predominant laminin isoforms in healthy adult skeletal muscle. Mutations in this chain result in progressive skeletal muscle degeneration as early as neonatally. Laminin-211/221 is a ligand for muscle cell receptors integrin-α7β1 and α-dystroglycan. LAMA2 mutations are correlated with integrin-α7β1 disruption in skeletal muscle.
    • (2020). "Laminin and Integrin in LAMA2-Related Congenital Muscular Dystrophy: From Disease to Therapeutics". Frontiers in Molecular Neuroscience 13. DOI:10.3389/fnmol.2020.00001.
  • The research on laminin α2 chain-deficient congenital muscular dystrophy (LAMA2-CMD) advanced rapidly in the last few decades, largely due to availability of good mouse models for the disease and a strong interest in preclinical studies from scientists all over the world. These mouse models continue to provide a solid platform for understanding the LAMA2-CMD pathology. In addition, they enable researchers to test laborious, necessary routines, but also the most creative scientific approaches in order to design therapy for this devastating disorder.
    • (2020). "A Family of Laminin α2 Chain-Deficient Mouse Mutants: Advancing the Research on LAMA2-CMD". Frontiers in Molecular Neuroscience 13. DOI:10.3389/fnmol.2020.00059.
  • The capacity of pathogenic microorganisms to adhere to host cells and avoid clearance by the host immune system is the initial and most decisive step leading to infections. Bacteria have developed different strategies to attach to diverse host surface structures. One important strategy is the adhesion to extracellular matrix (ECM) proteins (e.g., collagen, fibronectin, laminin) that are highly abundant in connective tissue and basement membranes. Gram-negative bacteria express variable outer membrane proteins (adhesins) to attach to the host and to initiate the process of infection. Understanding the underlying molecular mechanisms of bacterial adhesion is a prerequisite for targeting this interaction by “anti-ligands” to prevent colonization or infection of the host. Future development of such “anti-ligands” (specifically interfering with bacteria-host matrix interactions) might result in the development of a new class of anti-infective drugs for the therapy of infections caused by multidrug-resistant Gram-negative bacteria. This review summarizes our current knowledge about the manifold interactions of adhesins expressed by Gram-negative bacteria with ECM proteins and the use of this information for the generation of novel therapeutic antivirulence strategies.
    • (2019). "Interaction with the host: The role of fibronectin and extracellular matrix proteins in the adhesion of Gram-negative bacteria". Medical Microbiology and Immunology 209 (3): 277–299. DOI:10.1007/s00430-019-00644-3.
  • In adult rat testes, the basement membrane is structurally constituted by laminin and collagen chains that lay adjacent to the blood-testis barrier (BTB). It plays a crucial scaffolding role to support spermatogenesis. On the other hand, laminin-333 comprised of laminin-α3/ß3/γ3 at the apical ES (ectoplasmic specialization, a testis-specific cell-cell adherens junction at the Sertoli cell-step 8–19 spermatid interface) expressed by spermatids serves as a unique cell adhesion protein that forms an adhesion complex with α6ß1-integrin expressed by Sertoli cells to support spermiogenesis. Emerging evidence has shown that biologically active fragments are derived from basement membrane and apical ES laminin chains through proteolytic cleavage mediated by matrix metalloproteinase 9 (MMP9) and MMP2, respectively. Two of these laminin bioactive fragments: one from the basement membrane laminin-α2 chain called LG3/4/5-peptide, and one from the apical ES laminin-γ3 chain known as F5-peptide, are potent regulators that modify cell adhesion function at the Sertoli-spermatid interface (i.e., apical ES) but also at the Sertoli cell-cell interface designated basal ES at the blood-testis barrier (BTB) with contrasting effects. These findings not only highlight the physiological significance of these bioactive peptides that create a local regulatory network to support spermatogenesis, they also open a unique area of research.
    • (2022). "A laminin-based local regulatory network in the testis that supports spermatogenesis". Seminars in Cell & Developmental Biology 121: 40–52. DOI:10.1016/j.semcdb.2021.03.025. 2021
  • Laminin, a non-collagenous glycoprotein present in the brain extracellular matrix, helps to maintain blood–brain barrier (BBB) integrity and regulation. Neuroinflammation can compromise laminin structure and function, increasing BBB permeability. ... We found that laminin may be a good indicator of BBB overall structural integrity, although changes in expression are dependent on the pathologic or experimental model used. In ischemic stroke, permanent vascular damage correlates with increased laminin expression (β and γ subunits), while transient damage correlates with reduced laminin expression (α subunits). Laminin was reduced in traumatic brain injury and cerebral hemorrhage studies but increased in multiple sclerosis and status epilepticus studies. Despite these observations, there is limited knowledge about the role played by different subunits or isoforms (such as 411 or 511) of laminin in maintaining structural architecture of the BBB under neuroinflammation.
    • (2022). "Laminin as a Biomarker of Blood–Brain Barrier Disruption under Neuroinflammation: A Systematic Review". International Journal of Molecular Sciences 23 (12). DOI:10.3390/ijms23126788.
  • Blood vessels in the central nervous system (CNS) are unique in having high electrical resistance and low permeability, which creates a selective barrier protecting sensitive neural cells within the CNS from potentially harmful components in the blood. The molecular basis of this blood–brain barrier (BBB) is found at the level of endothelial adherens and tight junction protein complexes, extracellular matrix (ECM) components of the vascular basement membrane (BM), and the influence of adjacent pericytes and astrocyte endfeet. Current evidence supports the concept that instructive cues from the BBB ECM are not only important for the development and maturation of CNS blood vessels, but they are also essential for the maintenance of vascular stability and BBB integrity. In this review, we examine the contributions of one of the most abundant ECM proteins, laminin to BBB integrity, and summarize how genetic deletions of different laminin isoforms or their integrin receptors impact BBB development, maturation, and stability.
    • (2022). "The impact of genetic manipulation of laminin and integrins at the blood–brain barrier". Fluids and Barriers of the CNS 19 (1). DOI:10.1186/s12987-022-00346-8.
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  •   Encyclopedic article on Laminin on Wikipedia
  •   The dictionary definition of laminin on Wiktionary
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