SEA domain proteolysis determines the functional composition of dystroglycan.

SEA domain proteolysis determines the functional composition of dystroglycan. Research Abstract Details 

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SEA domain proteolysis determines the functional composition of dystroglycan. Abstract Text:

Armin Akhavan,Silvia N Crivelli,Manisha Singh,Vishwanath R Lingappa,John L Muschler,

Post-translational modifications of the extracellular matrix receptor dystroglycan (DG) determine its functional state, and defects in these modifications are linked to muscular dystrophies and cancers. A prominent feature of DG biosynthesis is a precursor cleavage that segregates the ligand-binding and transmembrane domains into the noncovalently attached alpha- and beta-subunits. We investigate here the structural determinants and functional significance of this cleavage. We show that cleavage of DG elicits a conspicuous change in its ligand-binding activity. Mutations that obstruct this cleavage result in increased capacity to bind laminin, in part, due to enhanced glycosylation of alpha-DG. Reconstitution of DG cleavage in a cell-free expression system demonstrates that cleavage takes place in the endoplasmic reticulum, providing a suitable regulatory point for later processing events. Sequence and mutational analyses reveal that the cleavage occurs within a full SEA (sea urchin, enterokinase, agrin) module with traits matching those ascribed to autoproteolysis. Thus, cleavage of DG constitutes a control point for the modulation of its ligand-binding properties, with therapeutic implications for muscular dystrophies. We provide a structural model for the cleavage domain that is validated by experimental analysis and discuss this cleavage in the context of mucin protein and SEA domain evolution.

SEA domain proteolysis determines the functional composition of dystroglycan. Publishing Authors By Initials

A Akhavan,SN Crivelli,M Singh,VR Lingappa,JL Muschler,

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SEA domain proteolysis determines the functional composition of dystroglycan. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The FASEB journal : official publication of the Fe

VOLUME: 22

Page Numbers: 612-21

Journal Abbreviation: FASEB J.

ISSN: 1530-6860

DAY: 28

MONTH: 09

YEAR: 2007

SEA domain proteolysis determines the functional composition of dystroglycan. Information

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LANGUAGE: eng

NlmUniqueID: 8804484

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Grant and Affiliation Information for SEA domain proteolysis determines the functional composition of dystroglycan.

AFFILIATION: California Pacific Medical Center Research Institute, 475 Brannan St., Ste. 220, San Francisco, CA 94107, USA.

Country: United States

AGENCY: United States NCI

GRANT: R01 CA109579

ACRONYM: CA

MEDLINETA: FASEB J

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