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Laminins are afamily ofglycoproteins of theextracellular matrix of all animals. They are major constituents of thebasement membrane, namely thebasal lamina (the protein network foundation for most cells and organs). Laminins are vital to biological activity, influencingcell differentiation,migration, andadhesion.[1][2]
Laminins areheterotrimeric proteins with a highmolecular mass (~400 to ~900kDa) and possess three different chains (α, β, and γ) encoded by five, four, and threeparalogous genes in humans, respectively. The laminin molecules are named according to their chain composition, e.g. laminin-511 contains α5, β1, and γ1 chains.[3] Fourteen other chain combinations have been identifiedin vivo. The trimeric proteins intersect, composing a cruciform structure that is able to bind to other molecules of the extracellular matrix and cell membrane.[4] The three short arms have an affinity for binding to other laminin molecules, conducing sheet formation. The long arm is capable of binding to cells and helps anchor organized tissue cells to the basement membrane.
Laminins are integral to the structural scaffolding of almost every tissue of an organism—secreted and incorporated into cell-associated extracellular matrices. Theseglycoproteins are imperative to the maintenance and vitality of tissues; defective laminins can cause muscles to form improperly, leading to a form ofmuscular dystrophy, lethal skin blistering disease (junctional epidermolysis bullosa), and/or defects of the kidney filter (nephrotic syndrome).[5]
In humans, fifteen laminin trimers have been identified. The laminins are combinations of different alpha-, beta-, and gamma-chains.[6]
Laminins were previously numbered as they were discovered, i.e., laminin-1, laminin-2, laminin-3, etc., but the nomenclature was changed to describe which chains are present in eachisoform (laminin-111, laminin-211, etc.).[3] In addition, many laminins had common names before either laminin nomenclature was in place.[7][8]
| Old nomenclature | Old synonyms | Chain composition | New nomenclature |
|---|---|---|---|
| Laminin-1 | EHS laminin | α1β1γ1 | Laminin-111 |
| Laminin-2 | Merosin | α2β1γ1 | Laminin-211 |
| Laminin-3 | S-laminin | α1β2γ1 | Laminin-121 |
| Laminin-4 | S-merosin | α2β2γ1 | Laminin-221 |
| Laminin-5 / Laminin-5A | Kalinin, epiligrin, nicein, ladsin | α3Aβ3γ2 | Laminin-332 / Laminin-3A32 |
| Laminin-5B | α3Bβ3γ2 | Laminin-3B32 | |
| Laminin-6 / Laminin-6A | K-laminin | α3Aβ1γ1 | Laminin-311 / Laminin-3A11 |
| Laminin-7 / Laminin-7A | KS-laminin | α3Aβ2γ1 | Laminin-321 / Laminin-3A21 |
| Laminin-8 | α4β1γ1 | Laminin-411 | |
| Laminin-9 | α4β2γ1 | Laminin-421 | |
| Laminin-10 | Drosophila-like laminin | α5β1γ1 | Laminin-511 |
| Laminin-11 | α5β2γ1 | Laminin-521 | |
| Laminin-12 | α2β1γ3 | Laminin-213 | |
| Laminin-14 | α4β2γ3 | Laminin-423 | |
| α5β2γ2 | Laminin-522 | ||
| Laminin-15 | α5β2γ3 | Laminin-523 |
Laminins form independent networks and are associated withtype IV collagen networks viaentactin,[9]fibronectin,[10] andperlecan. The proteins also bind to cell membranes throughintegrins and otherplasma membrane molecules, such as thedystroglycan glycoprotein complex and Lutheran blood group glycoprotein.[4] Through these interactions, laminins critically contribute to cell attachment and differentiation, cell shape and movement, maintenance of tissue phenotype, and promotion of tissue survival.[4][6] Some of these biological functions of laminin have been associated with specific amino-acid sequences or fragments of laminin.[4] For example, thepeptide sequence [GTFALRGDNGDNGQ], which is located on the alpha-chain of laminin, promotes the adhesion of endothelial cells.[11]
Laminin alpha4 is distributed in a variety oftissues, includingperipheral nerves,dorsal root ganglion,skeletal muscle, and capillaries; in theneuromuscular junction, it is required forsynaptic specialisation.[12] Thestructure of the laminin-G domain has been predicted to resemble that ofpentraxin.[13]
Laminin-111 is a major substrate along which nerve axons will grow, both in vivo and in vitro. For example, it lays down a path that developingretinal ganglion cells follow on their way from theretina to thetectum. It is also often used as a substrate in cell culture experiments. The presence of laminin-111 can influence how the growth cone responds to other cues. For example, growth cones are repelled by netrin when grown on laminin-111 but are attracted to netrin when grown on fibronectin.[citation needed] This effect of laminin-111 probably occurs through a lowering of intracellular cyclic AMP.[citation needed]
Laminins are enriched at the lesion site after peripheral nerve injury and are secreted bySchwann cells. Neurons of theperipheral nervous system express integrin receptors that attach to laminins and promoteneuroregeneration after injury.[14]
Dysfunctional structure of one particular laminin, laminin-211, is the cause of one form ofcongenital muscular dystrophy.[15] Laminin-211 is composed ofα2,β1, andγ1 chains. This laminin's distribution includes the brain and muscle fibers. In muscle, it binds toalpha-dystroglycan andintegrin alpha7—beta1 via the G domain, and via the other end, it binds to theextracellular matrix.
Abnormal laminin-332, essential for epithelial cell adhesion to the basement membrane, leads tojunctional epidermolysis bullosa, characterized by generalized blisters, exuberant granulation tissue of the skin and mucosa, and pitted teeth.
Malfunctional laminin-521 in the kidney filter causes leakage of protein into the urine andnephrotic syndrome.[5]
Some of the laminin isoforms have been implicated incancer pathophysiology. The majority of transcripts that harbor aninternal ribosome entry site (IRES) are involved in cancer development via corresponding proteins. A crucial event in tumor progression, referred to as theepithelial-to-mesenchymal transition (EMT) allows carcinoma cells to acquire invasive properties. The translational activation of the extracellular matrix component laminin B1 (LAMB1) during EMT has been recently reported, suggesting an IRES-mediated mechanism. The IRES activity of LamB1 was determined by independent bicistronic reporter assays. Strong evidence excludes an impact of cryptic promoter or splice sites on IRES-driven translation of LamB1. Furthermore, no other LamB1 mRNA species arising from alternative transcription start sites or polyadenylation signals were detected that account for its translational control. Mapping of the LamB1 5'-untranslated region (UTR) revealed the minimal LamB1 IRES motif between -293 and -1 upstream of the start codon. RNA affinity purification demonstrated that the La protein interacts with the LamB1 IRES. This interaction and its regulation during EMT were confirmed by ribonucleoprotein immunoprecipitation. La is able to positively modulate LamB1 IRES translation, so LamB1 IRES is activated by binding to La which leads to translational upregulation during hepatocellular EMT.[16]
Together with other major components of the ECM, such ascollagens andfibronectin, laminins have been used to enhance mammaliancell culture, especially in the case of pluripotentstem cells, as well as some primary cell cultures, which can be difficult to propagate on other substrates. Two types of naturally-sourced laminins are commercially available: Laminin-111, extracted from mouse sarcomas, and laminin mixtures from human placenta, which may primarily correspond to laminin-211, 411, or 511, depending on the provider.[17] The various laminin isoforms are practically impossible to isolate from tissues in pure form due to extensive cross-linking and the need for harsh extraction conditions, such as proteolytic enzymes or low pH, that cause degradation. Therefore,recombinant laminins have been produced since the year 2000.[18] This made it possible to test if laminins could have a significant rolein vitro as they have in the human body. In 2008, two groups independently showed that mouse embryonic stem cells can be grown for months on top of recombinant laminin-511.[19][20] Later, Rodinet al. showed that recombinant laminin-511 can be used to create a xeno-free and defined cell culture environment to culture human pluripotent ES cells and human iPS cells.[21]
| Laminin Domain I | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | Laminin_I | ||||||||
| Pfam | PF06008 | ||||||||
| InterPro | IPR009254 | ||||||||
| |||||||||
| Laminin Domain II | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | Laminin_II | ||||||||
| Pfam | PF06009 | ||||||||
| InterPro | IPR010307 | ||||||||
| |||||||||
| Laminin B (Domain IV) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | Laminin_B | ||||||||
| Pfam | PF00052 | ||||||||
| InterPro | IPR000034 | ||||||||
| |||||||||
| Laminin EGF-like (Domains III and V) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 crystal structure of three consecutive laminin-type epidermal growth factor-like (le) modules of laminin gamma1 chain harboring the nidogen binding site | |||||||||
| Identifiers | |||||||||
| Symbol | Laminin_EGF | ||||||||
| Pfam | PF00053 | ||||||||
| Pfam clan | CL0001 | ||||||||
| InterPro | IPR002049 | ||||||||
| PROSITE | PDOC00021 | ||||||||
| SCOP2 | 1tle /SCOPe /SUPFAM | ||||||||
| |||||||||
| Laminin G domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 laminin alpha 2 chain lg4-5 domain pair, ca1 site mutant | |||||||||
| Identifiers | |||||||||
| Symbol | Laminin_G_1 | ||||||||
| Pfam | PF00054 | ||||||||
| Pfam clan | CL0004 | ||||||||
| InterPro | IPR012679 | ||||||||
| SCOP2 | 1qu0 /SCOPe /SUPFAM | ||||||||
| |||||||||
| Laminin G domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 the structure of the ligand-binding domain of neurexin 1beta: regulation of lns domain function by alternative splicing | |||||||||
| Identifiers | |||||||||
| Symbol | Laminin_G_2 | ||||||||
| Pfam | PF02210 | ||||||||
| Pfam clan | CL0004 | ||||||||
| InterPro | IPR012680 | ||||||||
| SMART | TSPN | ||||||||
| |||||||||
| Laminin N-terminal (Domain VI) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | Laminin_N | ||||||||
| Pfam | PF00055 | ||||||||
| Pfam clan | CL0202 | ||||||||
| InterPro | IPR008211 | ||||||||
| SMART | LamNT | ||||||||
| SCOP2 | 1klo /SCOPe /SUPFAM | ||||||||
| |||||||||
Laminins contain severalconservedprotein domains.
Laminins are trimeric molecules; laminin-1 is an alpha1 beta1 gamma1trimer. It has been suggested that thedomains I and II from laminin A, B1 and B2 may come together to form a triple helicalcoiled-coilstructure.[22]
The laminin B domain (also known as domain IV) is anextracellular module of unknown function. It is found in a number of differentproteins that include,heparan sulphateproteoglycan frombasement membrane, a laminin-like protein fromCaenorhabditis elegans and laminin. Laminin IV domain is not found in short laminin chains (alpha4 or beta3).
Beside different types of globulardomains each laminin subunit contains, in its first half, consecutiverepeats of about 60amino acids in length that include eight conservedcysteines.[23] The tertiary structure of this domain is remotely similar in itsN-terminus to that of theEGF-like module.[24][25] It is also known as a 'LE' or 'laminin-type EGF-like' domain. The number of copies of the laminin EGF-like domain in the different forms of laminins is highly variable; from 3 up to 22 copies have been found. Inmouse laminin gamma-1 chain, the seventh LE domain has been shown to be the only one thatbinds with a high affinity tonidogen.[26] The binding-sites are located on the surface within theloops C1-C3 and C5-C6.[24][25] Long consecutive arrays of laminin EGF-like domains in laminins form rod-like elements of limited flexibility, which determine the spacing in the formation of laminin networks ofbasement membranes.[27][28]
The laminin globular (G) domain, also known as the LNS (Laminin-alpha, Neurexin and Sex hormone-binding globulin) domain, is on average 177amino acids in length and can be found in one to six copies in various laminin family members as well as in a large number of otherextracellularproteins.[29] For example, all laminin alpha-chains have five laminin G domains, allcollagen family proteins have one laminin G domain, the CNTNAP proteins have four laminin G domains, while neurexin 1 and 2 each hold six laminin G domains. On average, approximately one quarter of the proteins that hold laminin G domains is taken up by these laminin G domains themselves. The smallest laminin G domain can be found in one of the collagen proteins (COL24A1; 77 AA) and the largest domain in TSPEAR (219 AA).
The exact function of the Laminin Gdomains has remained elusive, and a variety of binding functions has been ascribed to different Laminin G modules. For example, the laminin alpha1 and alpha2 chains each have fiveC-terminal laminin G domains, where only domains LG4 and LG5 containbinding sites for heparin,sulphatides and thecell surface receptordystroglycan.[30] Laminin G-containingproteins appear to have a wide variety of roles incell adhesion,signalling,migration, assembly anddifferentiation.
Basement membrane assembly is a cooperative process in which lamininspolymerise through their N-terminal domain (LN or domain VI) and anchor to thecell surface through their G domains.Netrins may also associate with this network through heterotypic LN domain interactions.[28] This leads tocell signalling throughintegrins and dystroglycan (and possibly other receptors) recruited to the adherent laminin. This LN domain-dependent self-assembly is considered to be crucial for the integrity of basement membranes, as highlighted bygenetic forms ofmuscular dystrophy containing the deletion of the LN module from the alpha 2 laminin chain.[31] The laminin N-terminal domain is found in all laminin and netrinsubunits except laminin alpha 3A, alpha 4 and gamma 2.
