Phosphorylated and unphosphorylated serine 13 of CDC37 stabilize distinct interactions between its client and HSP90 binding domains

Wenjun Liu, Ralf Landgraf

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Folding and maturation of most protein kinases require chaperone assistance. In higher eukaryotes, CDC37 is the predominant cochaperone that facilitates the transfer of kinase clients to HSP90. Kinase recognition is thought to occur through the N-terminal domain, which has, thus far, eluded structure determination. Client processing also requires the phosphorylation of the N-terminal tail at Ser13 by protein kinase CK2 (casein kinase 2). How phosphorylation alters the molecular properties of CDC37 is not understood. We show that the phosphorylation at Ser13 induces a large shift toward a more compact structure, based on ANS fluorescence, while modestly increasing secondary structure. Moreover, this transition requires interactions of the N-terminal domain and the remainder of CDC37. The stabilizing property of the phosphorylation event can be recreated in trans by a (phospho-Ser13) peptide derived from the N-terminal tail. However, the phosphorylation-induced transition is not dependent on the transferred phosphate group but rather the loss of serine-like properties at position 13. The complete absence of the N-terminal tail results in reduced secondary structure and unresponsiveness to subsequent addition of peptides. The N-terminal tail may therefore serve as an intramolecular chaperone that ensures that CDC37 assumes one of two readily interconvertible states in a manner that impacts the interaction of the client binding N-domain and the MC-domains, involved in dimerization and HSP90 binding.

Original languageEnglish
Pages (from-to)1493-1504
Number of pages12
JournalBiochemistry
Volume54
Issue number7
DOIs
StatePublished - Feb 24 2015

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Phosphorylation
Serine
Protein Kinases
Phosphotransferases
Casein Kinase II
Peptides
Dimerization
Eukaryota
Fluorescence
Phosphates
Processing

ASJC Scopus subject areas

  • Biochemistry

Cite this

Phosphorylated and unphosphorylated serine 13 of CDC37 stabilize distinct interactions between its client and HSP90 binding domains. / Liu, Wenjun; Landgraf, Ralf.

In: Biochemistry, Vol. 54, No. 7, 24.02.2015, p. 1493-1504.

Research output: Contribution to journalArticle

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