title: Regulation of the CUL3 Ubiquitin Ligase by a Calcium-Dependent Co-adaptor.
abstract: The ubiquitin ligase CUL3 is an essential regulator of neural crest specification whose aberrant activation has been linked to autism, schizophrenia, and hypertension. CUL3 exerts its roles by pairing with ∼90 distinct substrate adaptors, yet how the different CUL3-complexes are activated is poorly understood. Here, we show that CUL3 and its adaptor KLHL12 require two calcium-binding proteins, PEF1 and ALG2, for recognition of their substrate SEC31. PEF1 and ALG2 form a target-specific co-adaptor that translates a transient rise in cytosolic calcium levels into more persistent SEC31 ubiquitylation, which in turn triggers formation of large COPII coats and promotes collagen secretion. As calcium also instructs chondrocyte differentiation and collagen synthesis, calcium-dependent control of CUL3KLHL12integrates collagen secretion into broader programs of craniofacial bone formation. Our work, therefore, identifies both calcium and CUL3 co-adaptors as important regulators of ubiquitylation events that control human development.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Colleen A
authors.initials: CA
authors.lastname: McGourty
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: David
authors.initials: D
authors.lastname: Akopian
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Walsh
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Amita
authors.initials: A
authors.lastname: Gorur
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Achim
authors.initials: A
authors.lastname: Werner
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Randy
authors.initials: R
authors.lastname: Schekman
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Bautista
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: mrape@berkeley.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Rape
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D022181:COP-Coated Vesicles / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D044842:Cullin Proteins / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D013379:Substrate Specificity; D054875:Ubiquitination; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C503645:CUL3 protein, human; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C493279:KLHL12 protein, human; D008840:Microfilament Proteins; C117020:PDCD6IP protein, human; C121810:PEF1 protein, human; C507455:SEC31A protein, human; D033921:Vesicular Transport Proteins; D003094:Collagen; D002118:Calcium
keywords: CUL3; SEC31; calcium; endoplasmic reticulum; ubiquitin