3J2Q

Model of membrane-bound factor VIII organized in 2D crystals

Summary for 3J2Q

• Entry DOI: 10.2210/pdb3j2q/pdb
• Related: 3CDZ
• Descriptor: Coagulation factor VIII heavy chain, Coagulation factor VIII light chain, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: blood coagulation, cofactor, factor viii, hemophilia, blood clotting
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 167247.95

Authors

Stoilova-Mcphie, S.,Lynch, G.C.,Ludtke, S.,Pettitt, B.M. (deposition date: 2012-12-11, release date: 2013-09-11, Last modification date: 2024-11-20)

Primary citation

Stoilova-McPhie, S.,Lynch, G.C.,Ludtke, S.,Pettitt, B.M.
Domain organization of membrane-bound factor VIII.
Biopolymers, 99:448-459, 2013

PubMed Abstract: 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.

PubMed: 23616213
DOI: 10.1002/bip.22199

Experimental method

ELECTRON CRYSTALLOGRAPHY (15 Å)