Crystal Structures of the Network-Forming Short-Arm Tips of the Laminin β1 and γ1 Chains

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

doi:10.1371/journal.pone.0042473

Cited by 52 publications

(93 citation statements)

References 45 publications

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“…Most of the cross-linked peptides were in the coiled coil, but some were within or between globular domains and in the EGF-like repeats. Crystal structures of laminin fragments (14,15,17,18) were used to assess the quality of the cross-linking results (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

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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“…27,28 It shows that the respective polypeptides are similarly arranged in a β-sandwich with elaborate loop regions that differ between laminin chains, and that, together with adjacent LE domains, the shape resembles the head and stalk of a flower. 27,28 The LE domains comprise 41 to 70 residues each, containing 8 cysteine residues, except in a few cases. Disulfide bonds between cysteine pairs 1 and 3, 2 and 4, and 5 and 6, determine the formation of loops a to c like in EGF.…”

Section: An Organized Patchwork Of a Few Structurally Distinct Domainmentioning

confidence: 99%

The laminin family

Aumailley

2013

Cell Adhesion & Migration

361

320

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Laminins are large molecular weight glycoproteins constituted by the assembly of three disulfide-linked polypeptides, the a, b and c 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.

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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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Crystal Structures of the Network-Forming Short-Arm Tips of the Laminin β1 and γ1 Chains

Cited by 52 publications

References 45 publications

Cross-linking reveals laminin coiled-coil architecture

Cross-linking reveals laminin coiled-coil architecture

The laminin family

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

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