Document Detail

Domain organization of membrane-bound factor VIII.
MedLine Citation:
PMID:  23616213     Owner:  NLM     Status:  In-Data-Review    
Factor VIII (FVIII) is the blood coagulation protein which when defective or deficient causes for hemophilia A, a severe hereditary bleeding disorder. Activated FVIII (FVIIIa) is the cofactor to the serine protease factor IXa (FIXa) within the membrane-bound Tenase complex, responsible for amplifying its proteolytic activity more than 100,000 times, necessary for normal clot formation. FVIII is composed of two noncovalently linked peptide chains: a light chain (LC) holding the membrane interaction sites and a heavy chain (HC) holding the main FIXa interaction sites. The interplay between the light and heavy chains (HCs) in the membrane-bound state is critical for the biological efficiency of FVIII. Here, we present our cryo-electron microscopy (EM) and structure analysis studies of human FVIII-LC, when helically assembled onto negatively charged single lipid bilayer nanotubes. The resolved FVIII-LC membrane-bound structure supports aspects of our previously proposed FVIII structure from membrane-bound two-dimensional (2D) crystals, such as only the C2 domain interacts directly with the membrane. The LC is oriented differently in the FVIII membrane-bound helical and 2D crystal structures based on EM data, and the existing X-ray structures. This flexibility of the FVIII-LC domain organization in different states is discussed in the light of the FVIIIa-FIXa complex assembly and function. © 2013 Wiley Periodicals, Inc. Biopolymers 99: 448-459, 2013.
Svetla Stoilova-McPhie; Gillian C Lynch; Steven Ludtke; B Montgomery Pettitt
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Biopolymers     Volume:  99     ISSN:  0006-3525     ISO Abbreviation:  Biopolymers     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-04-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0372525     Medline TA:  Biopolymers     Country:  United States    
Other Details:
Languages:  eng     Pagination:  448-59     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Wiley Periodicals, Inc.
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX.
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