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J Biol Chem, Vol. 274, Issue 49, 34515-34518, December 3, 1999

COMMUNICATION
Temperature-sensitive ZAP70 Mutants Degrading through a Proteasome-independent Pathway
RESTORATION OF A KINASE DOMAIN MUTANT BY Cdc37

Satoshi Matsuda, Tomoko Suzuki-Fujimoto, Akiko Minowa, Hideki Ueno^§, Kenji Katamura^§, and Shigeo Koyasu

From the  Department of Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan and the ^§ Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan

CD8 deficiency is an autosomal recessive form of severe combined immunodeficiency diseases characterized by the absence of CD8⁺ T lymphocytes and impaired T cell functions. We identified two novel mis-sense mutations in the zap70 genes of a CD8-deficiency patient. One mutation (P80Q) affects a residue in an SH2 domain and another (M572L) in the kinase subdomain XI. Both mutations cause a degradation of ZAP70 protein in a temperature-sensitive manner through an ATP-dependent and proteasome-independent pathway. We further demonstrated that Cdc37, a protein kinase-specific chaperone, bound to M572L but not P80Q mutant and restored the expression of the M572L mutant when overexpressed. The restoration of M572L mutant by Cdc37 required the function of HSP90. These results indicate that Cdc37 in conjunction with HSP90 functions as a molecular chaperone for a temperature-sensitive kinase domain mutant of ZAP70.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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