Abstract
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 pac2Delta 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. pac2Delta 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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Sequence
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cytoskeleton / genetics
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Cytoskeleton / metabolism
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Dimerization
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F-Box Proteins / genetics
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F-Box Proteins / metabolism
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F-Box-WD Repeat-Containing Protein 7
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Humans
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Hypoparathyroidism / genetics*
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Hypoparathyroidism / metabolism
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Intellectual Disability / genetics
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Intellectual Disability / metabolism
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Intracellular Signaling Peptides and Proteins
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Microtubules / genetics
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Microtubules / metabolism*
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Molecular Chaperones* / genetics
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Molecular Chaperones* / metabolism
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Molecular Chaperones* / physiology
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Mutation
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism*
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Proteins / genetics
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Proteins / metabolism
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Syndrome
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Tubulin / genetics
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Tubulin / metabolism*
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Ubiquitin / genetics
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
Substances
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Cell Cycle Proteins
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F-Box Proteins
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F-Box-WD Repeat-Containing Protein 7
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FBXW7 protein, human
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Intracellular Signaling Peptides and Proteins
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LGI1 protein, human
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Molecular Chaperones
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Proteins
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Tubulin
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Ubiquitin
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Ubiquitin-Protein Ligases
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Proteasome Endopeptidase Complex