Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 67, Issue 12, Pages 2025-2038Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-010-0308-8
Keywords
Pac2; CAP-Gly; Ubiquitin-like domain; Rpn1; Rpn10; Proteasome; TBCE
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Funding
- German-Israel Foundation for Scientific Research and Development (GIF) [1043/09]
- EU [HPRN-CT-2002-00238]
- Israel Cancer Research Fund (ICRF)
- Israel Cancer Association
- Israel-US Bi-National [2003141, 2005525]
- National Institute of Biotechnology, Negev
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Mutation of tubulin chaperone E (TBCE) underlies hypoparathyroidism, retardation, and dysmorphism (HRD) syndrome with defective microtubule (MT) cytoskeleton. TBCE/yeast Pac2 comprises CAP-Gly, LRR (leucine-rich region), and UbL (ubiquitin-like) domains. TBCE folds alpha-tubulin and promotes alpha/beta dimerization. We show that Pac2 functions in MT dynamics: the CAP-Gly domain binds alpha-tubulin and MTs, and functions in suppression of benomyl sensitivity of pac2 Delta mutants. Pac2 binds proteasomes: the LRR binds Rpn1, and the UbL binds Rpn10; the latter interaction mediates Pac2 turnover. The UbL also binds the Skp1-Cdc53-F-box (SCF) ubiquitin ligase complex; these competing interactions for the UbL may impact on MT dynamics. pac2 Delta mutants are sensitive to misfolded protein stress. This is suppressed by ectopic PAC2 with both the CAP-Gly and UbL domains being essential. We propose a novel role for Pac2 in the misfolded protein stress response based on its ability to interact with both the MT cytoskeleton and the proteasomes.
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