6snk

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Crystal structure of the Collagen VI alpha3 N2 domain

Structural highlights

6snk is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.2Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CO6A3_HUMAN Defects in COL6A3 are a cause of Bethlem myopathy (BM) [MIM:158810. BM is a rare autosomal dominant proximal myopathy characterized by early childhood onset (complete penetrance by the age of 5) and joint contractures most frequently affecting the elbows and ankles.[1] [2] [3] [4] [5] Defects in COL6A3 are a cause of Ullrich congenital muscular dystrophy (UCMD) [MIM:254090; also known as Ullrich scleroatonic muscular dystrophy. UCMD is an autosomal recessive congenital myopathy characterized by muscle weakness and multiple joint contractures, generally noted at birth or early infancy. The clinical course is more severe than in Bethlem myopathy.[6] [7]

Function

CO6A3_HUMAN Collagen VI acts as a cell-binding protein.

Publication Abstract from PubMed

Collagen VI is a ubiquitous heterotrimeric protein of the extracellular matrix (ECM) that plays an essential role in the proper maintenance of skeletal muscle. Mutations in collagen VI lead to a spectrum of congenital myopathies, from the mild Bethlem Myopathy to the severe Ullrich Congenital Muscular Dystrophy. Collagen VI contains only a short triple helix and consists primarily of von Willebrand Factor type A (VWA) domains, protein-protein interaction modules found in a range of ECM proteins. Disease causing mutations occur commonly in the VWA domains, and the second VWA domain of the alpha3 chain, the N2 domain, harbors several such mutations. Here, we investigate structure-function relationships of the N2 mutations to shed light on their possible myopathy mechanisms. We determined the X-ray crystal structure of N2, combined with monitoring secretion efficiency in cell culture of selected N2 single domain mutants, finding that mutations located within the central core of the domain severely affect secretion efficiency. In longer alpha3 chain constructs, spanning N6-N3, small-angle X-ray scattering demonstrates that the tandem VWA array has a modular architecture and samples multiple conformations in solution. Single particle EM confirmed the presence of multiple conformations. Structural adaptability appears intrinsic to the VWA domain region of collagen VI alpha3 and has implications for binding interactions and modulating stiffness within the ECM.

Structure of a collagen VI alpha3 chain VWA domain array: adaptability and functional implications of myopathy causing mutations.,Solomon-Degefa H, Gebauer JM, Jeffries CM, Freiburg CD, Meckelburg P, Bird LE, Baumann U, Svergun DI, Owens RJ, Werner JM, Behrmann E, Paulsson M, Wagener R J Biol Chem. 2020 Jul 21. pii: RA120.014865. doi: 10.1074/jbc.RA120.014865. PMID:32719005[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
0 reviews cite this structure
Collagen VI Muscle Disorders: Mutation Types, Pathogenic Mechanisms and Approaches to Therapy.
Lamandé et al. (2021)
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2 other articles
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References

  1. ↑ Demir E, Sabatelli P, Allamand V, Ferreiro A, Moghadaszadeh B, Makrelouf M, Topaloglu H, Echenne B, Merlini L, Guicheney P. Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy. Am J Hum Genet. 2002 Jun;70(6):1446-58. Epub 2002 Apr 24. PMID:11992252 doi:S0002-9297(07)60697-1
  2. ↑ Pan TC, Zhang RZ, Pericak-Vance MA, Tandan R, Fries T, Stajich JM, Viles K, Vance JM, Chu ML, Speer MC. Missense mutation in a von Willebrand factor type A domain of the alpha 3(VI) collagen gene (COL6A3) in a family with Bethlem myopathy. Hum Mol Genet. 1998 May;7(5):807-12. PMID:9536084
  3. ↑ Pepe G, Bertini E, Giusti B, Brunelli T, Comeglio P, Saitta B, Merlini L, Chu ML, Federici G, Abbate R. A novel de novo mutation in the triple helix of the COL6A3 gene in a two-generation Italian family affected by Bethlem myopathy. A diagnostic approach in the mutations' screening of type VI collagen. Neuromuscul Disord. 1999 Jun;9(4):264-71. PMID:10399756
  4. ↑ Lampe AK, Dunn DM, von Niederhausern AC, Hamil C, Aoyagi A, Laval SH, Marie SK, Chu ML, Swoboda K, Muntoni F, Bonnemann CG, Flanigan KM, Bushby KM, Weiss RB. Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy. J Med Genet. 2005 Feb;42(2):108-20. PMID:15689448 doi:42/2/108
  5. ↑ Baker NL, Morgelin M, Pace RA, Peat RA, Adams NE, Gardner RJ, Rowland LP, Miller G, De Jonghe P, Ceulemans B, Hannibal MC, Edwards M, Thompson EM, Jacobson R, Quinlivan RC, Aftimos S, Kornberg AJ, North KN, Bateman JF, Lamande SR. Molecular consequences of dominant Bethlem myopathy collagen VI mutations. Ann Neurol. 2007 Oct;62(4):390-405. PMID:17886299 doi:10.1002/ana.21213
  6. ↑ Demir E, Sabatelli P, Allamand V, Ferreiro A, Moghadaszadeh B, Makrelouf M, Topaloglu H, Echenne B, Merlini L, Guicheney P. Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy. Am J Hum Genet. 2002 Jun;70(6):1446-58. Epub 2002 Apr 24. PMID:11992252 doi:S0002-9297(07)60697-1
  7. ↑ Lampe AK, Dunn DM, von Niederhausern AC, Hamil C, Aoyagi A, Laval SH, Marie SK, Chu ML, Swoboda K, Muntoni F, Bonnemann CG, Flanigan KM, Bushby KM, Weiss RB. Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy. J Med Genet. 2005 Feb;42(2):108-20. PMID:15689448 doi:42/2/108
  8. ↑ Solomon-Degefa H, Gebauer JM, Jeffries CM, Freiburg CD, Meckelburg P, Bird LE, Baumann U, Svergun DI, Owens RJ, Werner JM, Behrmann E, Paulsson M, Wagener R. Structure of a collagen VI alpha3 chain VWA domain array: adaptability and functional implications of myopathy causing mutations. J Biol Chem. 2020 Jul 21. pii: RA120.014865. doi: 10.1074/jbc.RA120.014865. PMID:32719005 doi:http://dx.doi.org/10.1074/jbc.RA120.014865

Contents


PDB ID 6snk

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