Surface charge and hydrophobicity determine ErbB2 binding to the Hsp90 chaperone complex.
The molecular chaperone Hsp90 modulates the function of specific cell signaling proteins. Although targeting Hsp90 with the antibiotic inhibitor geldanamycin (GA) may be a promising approach for cancer treatment, little is known about the determinants of Hsp90 interaction with its client proteins. Here we identify a loop within the N lobe of the kinase domain of ErbB2 that determines Hsp90 binding. The amino acid sequence of the loop determines the electrostatic and hydrophobic character of the protein's surface, which in turn govern interaction with Hsp90. A point mutation within the loop that alters ErbB2 surface properties disrupts Hsp90 association and confers GA resistance. Notably, the immature ErbB2 point mutant remains sensitive to GA, suggesting that mature and nascent client kinases may use distinct motifs to interact with the Hsp90 chaperone complex.
Xu
Wanping
W
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Rockville, Maryland 20850, USA.
Yuan
Xitong
X
Xiang
Zhexin
Z
Mimnaugh
Edward
E
Marcu
Monica
M
Neckers
Len
L
D000818:Animals; D016227:Benzoquinones; D019556:COS Cells; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D047029:Lactams, Macrocyclic; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011809:Quinones / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D055672:Static Electricity
D016227:Benzoquinones; D066246:ErbB Receptors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D046912:Multiprotein Complexes; D011809:Quinones; D018719:Erb-b2 Receptor Tyrosine Kinases; C001277:geldanamycin