Structure of an ultraweak protein-protein complex and its crucial role in regulation of cell morphology and motility.
Weak protein-protein interactions (PPIs) (K(D) > 10(-6) M) are critical determinants of many biological processes. However, in contrast to a large growing number of well-characterized, strong PPIs, the weak PPIs, especially those with K(D) > 10(-4) M, are poorly explored. Genome wide, there exist few 3D structures of weak PPIs with K(D) > 10(-4) M, and none with K(D) > 10(-3) M. Here, we report the NMR structure of an extremely weak focal adhesion complex (K(D) approximately 3 x 10(-3) M) between Nck-2 SH3 domain and PINCH-1 LIM4 domain. The structure exhibits a remarkably small and polar interface with distinct binding modes for both SH3 and LIM domains. Such an interface suggests a transient Nck-2/PINCH-1 association process that may trigger rapid focal adhesion turnover during integrin signaling. Genetic rescue experiments demonstrate that this interface is indeed involved in mediating cell shape change and migration. Together, the data provide a molecular basis for an ultraweak PPI in regulating focal adhesion dynamics during integrin signaling.
Vaynberg
Julia
J
Structural Biology Program, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Fukuda
Tomohiko
T
Chen
Ka
K
Vinogradova
Olga
O
Velyvis
Algirdas
A
Tu
Yizeng
Y
Ng
Lily
L
Wu
Chuanyue
C
Qin
Jun
J
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D001665:Binding Sites; D002465:Cell Movement; D048430:Cell Shape; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D022001:Focal Adhesions; D006367:HeLa Cells; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D060588:LIM Domain Proteins; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D025941:Protein Interaction Mapping; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D001324:Autoantigens; D004268:DNA-Binding Proteins; D016023:Integrins; D060588:LIM Domain Proteins; C088088:LIMS1 protein, human; C490232:Lims1 protein, mouse; D008565:Membrane Proteins; C485544:NCK2 protein, human; C117758:Nck2 protein, mouse; D015513:Oncogene Proteins