Journal Article

PUBDB-2017-14024

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structural flexibility of human $\alpha$-dystroglycan

Covaceuszach, S. (Corresponding author)Extern* ; Bozzi, M. ; Bigotti, M. G. ; Sciandra, F. ; Konarev, P. V. ; Brancaccio, A. (Corresponding author) ; Cassetta, A.

2017
Elsevier on behalf of the Federation of European Biochemical Societies Cambridge

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Please use a persistent id in citations: doi:10.1002/2211-5463.12259

Abstract: Dystroglycan (DG), composed of a and b subunits, belongs to the dys-trophin-associated glycoprotein complex. $^a$-DG is an extracellular matrix protein that undergoes a complex post-translational glycosylation process. The bifunctional glycosyltransferase like-acetylglucosaminyltransferase (LARGE) plays a crucial role in the maturation of $^a$-DG, enabling its binding to laminin. We have already structurally analyzed the N-terminal region of murine $^a$-DG ($^a$-DG-Nt) and of a pathological single point mutant that may affect recognition of LARGE, although the structural features of the potential interaction between LARGE and DG remain elusive. We now report on the crystal structure of the wild-type human $^a$-DG-Nt that has allowed us to assess the reliability of our murine crystallographic structure as a $^a$-DG-Nt general model. Moreover, we address for the first time both structures in solution. Interestingly, small-angle X-ray scattering (SAXS) reveals the existence of two main protein conformations ensembles. The predominant species is reminiscent of the crystal structure, while the less populated one assumes a more extended fold. A comparative analysis of the human and murine $^a$-DG-Nt solution structures reveals that the two proteins share a common interdomain flexibility and population distribution of the two conformers. This is confirmed by the very similar stability displayed by the two orthologs as assessed by biochemical and biophysical experiments. These results highlight the need to take into account the molecular plasticity of $^a$-DG-Nt in solution, as it can play an important role in the functional interactions with other binding partners.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (POF3-622) (POF3-622)

Experiment(s):

1. PETRA Beamline P12 (PETRA III)

Appears in the scientific report 2017

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Database coverage:
; ; ; BIOSIS Previews ; DOAJ Seal ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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