Determinants of laminin polymerization revealed by the structure of the α5 chain amino‐terminal region

Hussain, Sadaf-Ahmahni; Carafoli, Federico; Hohenester, Erhard

doi:10.1038/embor.2011.3

Cited by 64 publications

(130 citation statements)

References 26 publications

(32 reference statements)

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“…4). Human α2LN domain mutations with retained Lmα2 subunit expression include Y138H, Q167P, L243P, and G248R, which are located on a polymerization face identified in α2LN domain (4,5). Patients with this type of mutation have little-to-modest reduced protein levels present, with a milder limb-girdle-type dystrophy, in which ambulation is achieved (3,6,7).…”

Section: Introductionmentioning

confidence: 99%

“…Loss of the transgene benefit corresponded to the development of permanent hind limb extension contractures, which are the result of prominent peripheral neuropathy, a phenotype that is not affected by expression of the transgene in skeletal muscle. When all limbs were evaluated together, the small initial reduction of grip strength in dy2J mice became maximal by 5 weeks of age, with transgene expression associated with an improvement in grip strength of approximately 50% compared with that of controls, reflecting full recovlaminin network, linking the laminins and their receptor-and matrix-binding partners into a cohesive unit (5,(17)(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Chimeric protein repair of laminin polymerization ameliorates muscular dystrophy phenotype

McKee¹,

Crosson²,

Meinen³

et al. 2017

Journal of Clinical Investigation

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chimeric protein repair of laminin polymerization ameliorates muscular dystrophy phenotype

McKee¹,

Crosson²,

Meinen³

et al. 2017

Journal of Clinical Investigation

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“…Due to the centrality of laminin in cell-ECM interactions, efforts have been made to analyze the functional regions of the trimer, to determine which α, β, and γ paralogs associate into physiological heterotrimers and to understand how trimers self-assemble into higher-order networks. Laminin fragments have been generated to assess their binding properties (11, 12) and as targets for structure determination by X-ray crystallography (13)(14)(15)(16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

Cross-linking reveals laminin coiled-coil architecture

Armony

Jacob

Moran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Laminin, an ∼800-kDa heterotrimeric protein, is a major functional component of the extracellular matrix, contributing to tissue development and maintenance. The unique architecture of laminin is not currently amenable to determination at high resolution, as its flexible and narrow segments complicate both crystallization and single-particle reconstruction by electron microscopy. Therefore, we used cross-linking and MS, evaluated using computational methods, to address key questions regarding laminin quaternary structure. This approach was particularly well suited to the ∼750-Å coiled coil that mediates trimer assembly, and our results support revision of the subunit order typically presented in laminin schematics. Furthermore, information on the subunit register in the coiled coil and cross-links to downstream domains provide insights into the self-assembly required for interaction with other extracellular matrix and cell surface proteins.L aminins are network-forming constituents of the extracellular matrix (ECM) (1, 2). They interact with the cell surface and other ECM components to generate a physical and functional framework affecting cell viability, identity, and activity. The laminin family appears to have arisen during the evolution of multicellularity in animals (3), and laminins contribute to a diversity of basement membrane and connective tissue structures in mammals (2). Laminins are studied in the context of development (4), stem cell biology (5), tissue engineering (6), cancer (7), and aging (8). The remarkable structural organization of laminins underlies their important physiological functions.Laminins are composed of three subunits, α, β, and γ, that assemble into a roughly humanoid form as visualized using rotary shadowing electron microscopy (9). The individual subunits separately form the "head" and two "arms," which are composed of epidermal growth factor (EGF)-like cysteine-rich repeats with globular domains embedded (10) (Fig. 1). Following the head and arms, the three subunits come together to form a long coiled coil, constituting the "body." Additional globular domains unique to the α subunit are the "feet." The laminin head and arms may splay to form a tripod (2), a feature not captured in rotary shadowing images or in diagrams of domain composition. Due to the centrality of laminin in cell-ECM interactions, efforts have been made to analyze the functional regions of the trimer, to determine which α, β, and γ paralogs associate into physiological heterotrimers and to understand how trimers self-assemble into higher-order networks. Laminin fragments have been generated to assess their binding properties (11, 12) and as targets for structure determination by X-ray crystallography (13)(14)(15)(16)(17)(18)(19)(20).Despite this progress, few insights into the overall 3D architecture of laminin have been made in the past few decades, and certain regions of the complex have been neglected as targets of structural techniques. In particular, no structure has been determined for any segment of th...

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“…Therefore, the deleterious pathological consequences in zebrafish may, of course, also reflect the disruption of a disulfide bridge that is important for the tertiary structure of LN domain. Because there is currently no high-resolution information available for the hLM α-1 N, homology models calculated with Phyre2 [24], HHpred [51] and M4T [11] servers and template pdb files -4AQS [6], 4PLO [57], 3ZYJ [49], and 2Y38 [20], have been used to reveal that the cysteine residue in question (C49) is involved in one of three disulfide bridges in the LN domain. Fig.…”

Section: Discussionmentioning

confidence: 99%

“…7. Homology model of hLM α-1 N-terminal globular domain calculated using Phyre2 [24] server and templates pdb files -4AQS, 4AQT [6], 4PLO [57], 3ZYJ [49], and 2Y38 [20]. Blue sticks identify two of the disulfide bridges, whereas the third bridge, between C49 (corresponding to C56 in zebrafish) and C65 (corresponding to C72 in zebrafish), is identified by highlighting the respective residues in red and magenta.…”

Section: Discussionmentioning

confidence: 99%

Biophysical analysis of a lethal laminin alpha-1 mutation reveals altered self-interaction

et al. 2016

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CitationPatel TR, Nikodemus D, Besong TMD, Reuten R, Meier M, et al. (2015) Biophysical analysis of a lethal laminin alpha-1 mutation reveals altered self-interaction. Matrix Biology. AbstractLaminins are key basement membrane molecules that influence several biological activities and are linked to a number of diseases. They are secreted as heterotrimeric proteins consisting of one α, one β, and one γ chain, followed by their assembly into a polymer-like sheet at the basement membrane. Using sedimentation velocity, dynamic light scattering, and surface plasmon resonance experiments, we studied self-association of three laminin (LM) N-terminal fragments α-1 (hLM α-1 N), α-5 (hLM α-5 N) and β-3 (hLM β-3 N) originating from the short arms of the human laminin αβγ heterotrimer. Corresponding studies of the hLM α-1 N C49S mutant, equivalent to the larval lethal C56S mutant in zebrafish, have shown that this mutation causes enhanced self-association behavior, an observation that provides a plausible explanation for the inability of laminin bearing this mutation to fulfill functional roles in vivo, and hence for the deleterious pathological consequences of the mutation on lens function.

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Determinants of laminin polymerization revealed by the structure of the α5 chain amino‐terminal region

Cited by 64 publications

References 26 publications

Chimeric protein repair of laminin polymerization ameliorates muscular dystrophy phenotype

Chimeric protein repair of laminin polymerization ameliorates muscular dystrophy phenotype

Cross-linking reveals laminin coiled-coil architecture

Biophysical analysis of a lethal laminin alpha-1 mutation reveals altered self-interaction

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