Structure of the split PH domain and distinct lipid-binding properties of the PH-PDZ supramodule of alpha-syntrophin.
Pleckstrin homology (PH) domains play diverse roles in cytoskeletal dynamics and signal transduction. Split PH domains represent a unique subclass of PH domains that have been implicated in interactions with complementary partial PH domains 'hidden' in many proteins. Whether partial PH domains exist as independent structural units alone and whether two halves of a split PH domain can fold together to form an intact PH domain are not known. Here, we solved the structure of the PH(N)-PDZ-PH(C) tandem of alpha-syntrophin. The split PH domain of alpha-syntrophin adopts a canonical PH domain fold. The isolated partial PH domains of alpha-syntrophin, although completely unfolded, remain soluble in solution. Mixing of the two isolated domains induces de novo folding and yields a stable PH domain. Our results demonstrate that two complementary partial PH domains are capable of binding to each other to form an intact PH domain. We further showed that the PH(N)-PDZ-PH(C) tandem forms a functionally distinct supramodule, in which the split PH domain and the PDZ domain function synergistically in binding to inositol phospholipids.
Yan
Jing
J
Department of Biochemistry, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Hong Kong, People's Republic of China.
Wen
Wenyu
W
Xu
Weiguang
W
Long
Jia-Fu
JF
Adams
Marvin E
ME
Froehner
Stanley C
SC
Zhang
Mingjie
M
D000818:Animals; D001665:Binding Sites; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D009124:Muscle Proteins / Q000737:chemistry* / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000737:chemistry / Q000378:metabolism*; D017510:Protein Folding; D017434:Protein Structure, Tertiary
D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D010716:Phosphatidylinositols; C091825:syntrophin alpha1