title: The STI and UBA Domains of UBQLN1 Are Critical Determinants of Substrate Interaction and Proteostasis.
abstract: There are five Ubiquilin proteins (UBQLN1-4, UBQLN-L), which are evolutionarily conserved and structurally similar. UBQLN proteins have three functional domains: N-terminal ubiquitin-like domain (UBL), C-terminal ubiquitin-associated domain (UBA), and STI chaperone-like regions in the middle. Alterations in UBQLN1 gene have been detected in a variety of disorders ranging from Alzheimer's disease to cancer. UBQLN1 has been largely studied in neurodegenerative disorders in the context of protein quality control. Several studies have hypothesized that the UBA domain of UBQLN1 binds to poly-ubiquitin chains of substrate and shuttles it to the proteasome via its UBL domain for degradation. UBQLN1 either facilitates degradation (Ataxin3, EPS15) or stabilizes (PSEN1/2, BCLb) substrates it binds to. The signal that determines this fate is unknown and there is conflicting data to support the existing working model of UBQLN1. Using BCLb as a model substrate, we characterized UBQLN1-substrate interaction. We identified the first two STI domains of UBQLN1 as critical for binding to BCLb. Interaction of UBQLN1 with BCLb is independent of ubiquitination of BCLb, but interaction with ubiquitin via UBA domain is required for stabilization of BCLb. Similarly, we showed that UBQLN1 interacts with IGF1R and ESYT2 through the STI domains and stabilizes these proteins through its UBA domain. Interactions that are not dependent on STI domains, for example, UBL mediated interaction with PSMD4 and BAG6, do not appear to be stabilized by UBQLN1. We conclude that fate of substrates that UBQLN1 associates with, is interaction domain specific. J. Cell. Biochem. 118: 2261-2270, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky.|Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Zimple
authors.initials: Z
authors.lastname: Kurlawala
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky.
authors.forename: Parag P
authors.initials: PP
authors.lastname: Shah
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky.
authors.forename: Charmi
authors.initials: C
authors.lastname: Shah
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky.|Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, Kentucky.|Division of Hematology and Oncology, School of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Levi J
authors.initials: LJ
authors.lastname: Beverly
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D000074702:Proteostasis / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; C092009:BAG6 protein, human; C428448:BCL2L14 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C000597236:IGF1R protein, human; D018832:Molecular Chaperones; C498506:PSMD4 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016601:RNA-Binding Proteins; D017451:Receptors, Somatomedin; C107792:UBQLN1 protein, human; D025801:Ubiquitin; D017526:Receptor, IGF Type 1; D046988:Proteasome Endopeptidase Complex
keywords: BAG6; BCLb; ESYT2; IGF1R; PROTEOSTASIS; PSMD4; STI; UBA; UBL; UBQLN