Cbl promotes clustering of endocytic adaptor proteins.
The ubiquitin ligases c-Cbl and Cbl-b play a crucial role in receptor downregulation by mediating multiple monoubiquitination of receptors and promoting their sorting for lysosomal degradation. Their function is modulated through interactions with regulatory proteins including CIN85 and PIX, which recognize a proline-arginine motif in Cbl and thus promote or inhibit receptor endocytosis. We report the structures of SH3 domains of CIN85 and beta-PIX in complex with a proline-arginine peptide from Cbl-b. Both structures reveal a heterotrimeric complex containing two SH3 domains held together by a single peptide. Trimerization also occurs in solution and is facilitated by the pseudo-symmetrical peptide sequence. Moreover, ternary complexes of CIN85 and Cbl are formed in vivo and are important for the ability of Cbl to promote epidermal growth factor receptor (EGFR) downregulation. These results provide molecular explanations for a novel mechanism by which Cbl controls receptor downregulation.
Jozic
Daniela
D
Division of Protein Structure, National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
Cárdenes
Nayra
N
Deribe
Yonathan Lissanu
YL
Moncalián
Gabriel
G
Hoeller
Daniela
D
Groemping
Yvonne
Y
Dikic
Ivan
I
Rittinger
Katrin
K
Bravo
Jerónimo
J
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism; D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D002151:Calorimetry; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism; D003460:Crystallization; D015536:Down-Regulation; D004705:Endocytosis / Q000235:genetics / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism; D004926:Escherichia coli; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D013329:Structure-Activity Relationship
C576606:ARHGEF7 protein, human; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors; C433810:SH3KBP1 protein, human; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; C067419:CBL protein, human