Structural flexibility regulates phosphopeptide-binding activity of the tyrosine kinase binding domain of Cbl-c.
Through their ubiquitin ligase activity, Cbl-family proteins suppress signalling mediated by protein-tyrosine kinases (PTKs), but can also function as adaptor proteins to positively regulate signalling. The tyrosine kinase binding (TKB) domain of this family is critical for binding with tyrosine-phosphorylated target proteins. Here, we analysed the crystal structure of the TKB domain of Cbl-c/Cbl-3 (Cbl-c TKB), which is a distinct member of the mammalian Cbl-family. In comparison with Cbl TKB, Cbl-c TKB showed restricted structural flexibility upon phosphopeptide binding. A mutation in Cbl-c TKB augmenting this flexibility enhanced its binding to target phosphoproteins. These results suggest that proteins, post-translational modifications or mutations that alter structural flexibility of the TKB domain of Cbl-family proteins could regulate their binding to target phosphoproteins and thereby, affect PTK-mediated signalling.
Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
Kohei
K
Takeshita
Tohru
T
Tezuka
Yukari
Y
Isozaki
Eiki
E
Yamashita
Mamoru
M
Suzuki
Minsoo
M
Kim
Yuji
Y
Yamanashi
Tadashi
T
Yamamoto
Atsushi
A
Nakagawa
D001665:Binding Sites; D002478:Cells, Cultured; D003460:Crystallization; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010748:Phosphopeptides / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*
D010748:Phosphopeptides; D050721:Proto-Oncogene Proteins c-cbl; D011505:Protein-Tyrosine Kinases