Fub1p, a novel protein isolated by boundary screening, binds the proteasome complex

Hatanaka, Akira; Chen, Bo; Sun, Jing-Qian; Mano, Yasunobu; Funakoshi, Mitsuaki; Kobayashi, Hideki; Ju, Young‐Tae; Mizutani, Tetsuya; Shinmyozu, Kaori; Nakayama, Jun‐ichi; Miyamoto, Kaoru; Uchida, Hiroyuki; Oki, Masaya

doi:10.1266/ggs.86.305

Cited by 16 publications

(12 citation statements)

References 53 publications

(71 reference statements)

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“…However, Blm10 also associates with mature proteasomes and has apparent functions beyond CP assembly[69–73]. Yeast Fub1 (human PI31), a proline-rich protein[74], has been reported to be associated with several CP subunits; loss of Fub1 exacerbates defects caused by mutations in proteasome subunits or assembly chaperones[75,76]. These data suggest a possible role of Fub1 in modulating proteasome assembly.…”

Section: The 20s Core Particle (Cp)mentioning

confidence: 99%

Proteasome Structure and Assembly

Budenholzer

Cheng

et al. 2017

Journal of Molecular Biology

303

280

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The eukaryotic 26S proteasome is a large multi-subunit complex that degrades the majority of proteins in the cell under normal conditions. The 26S proteasome can be divided into two subcomplexes: the 19S regulatory particle (RP) and the 20S core particle (CP). Most substrates are first covalently modified by ubiquitin, which then directs them to the proteasome. The function of the RP is to recognize, unfold, deubiquitylate and translocate substrates into the CP, which contains the proteolytic sites of the proteasome. Given the abundance and subunit complexity of the proteasome, the assembly of this ~2.5 MDa complex must be carefully orchestrated to ensure its correct formation. In recent years, significant advances have been made in the understanding of proteasome assembly, structure and function. Technical advances in cryo-electron microscopy have resulted in a series of atomic cryo-EM structures of both human and yeast 26S proteasomes. These structures have illuminated new intricacies and dynamics of the proteasome. In this review, we focus on the mechanisms of proteasome assembly, particularly in light of recent structural information.

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Section: The 20s Core Particle (Cp)mentioning

confidence: 99%

Proteasome Structure and Assembly

Budenholzer

Cheng

et al. 2017

Journal of Molecular Biology

303

280

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“…PI31 proteins are conserved among eukaryotes from yeast to mammals. Human PI31 (hPI31) shares approximately 20% amino acid identity with Fub1 (27). Taking advantage of the lethality of ⌬fub1 ⌬pba4, we examined whether hPI31 complements ⌬fub1.…”

Section: Fub1 Is Associated Mainly With the 20s Cpmentioning

confidence: 99%

“…This protein, named Fub1 (function of boundary), has been shown to associate with the CP subunits. Hatanaka et al also showed that FUB1/YCR076c exhibited genetic interactions with several proteasome-related genes, suggesting a functional relationship between the PI31 homolog and the proteasome in budding yeast (27). However,…”

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confidence: 99%

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N-Terminal α7 Deletion of the Proteasome 20S Core Particle Substitutes for Yeast PI31 Function

Yashiroda

Toda

Otsu

et al. 2015

Molecular and Cellular Biology

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The proteasome core particle (CP) is a conserved protease complex that is formed by the stacking of two outer ␣-rings and two inner ␤-rings. The ␣-ring is a heteroheptameric ring of subunits ␣1 to ␣7 and acts as a gate that restricts entry of substrate proteins into the catalytic cavity formed by the two abutting ␤-rings. The 31-kDa proteasome inhibitor (PI31) was originally identified as a protein that binds to the CP and inhibits CP activity in vitro, but accumulating evidence indicates that PI31 is required for physiological proteasome activity. To clarify the in vivo role of PI31, we examined the Saccharomyces cerevisiae PI31 ortholog Fub1. Fub1 was essential in a situation where the CP assembly chaperone Pba4 was deleted. The lethality of ⌬fub1 ⌬pba4 was suppressed by deletion of the N terminus of ␣7 (␣7⌬N), which led to the partial activation of the CP. However, deletion of the N terminus of ␣3, which activates the CP more efficiently than ␣7⌬N by gate opening, did not suppress ⌬fub1 ⌬pba4 lethality. These results suggest that the ␣7 N terminus has a role in CP activation different from that of the ␣3 N terminus and that the role of Fub1 antagonizes a specific function of the ␣7 N terminus. The 26S proteasome is a multicatalytic protease complex conserved in eukaryotes (1). Its main function is to serve as a selective and regulated mechanism for intracellular protein degradation, mainly in a ubiquitin-dependent manner. The 26S proteasome consists of one 20S core particle (CP) and one or two 19S regulatory particles (RPs) attached to the CP.The CP exerts proteolytic activity and is made up of four axially stacked heteroheptameric rings: two outer ␣-rings formed by ␣1 to ␣7 and two inner ␤-rings formed by ␤1 to ␤7. Of the seven ␤-subunits, only ␤1, ␤2, and ␤5 have proteolytic activities. The archaebacterium Thermoplasma acidophilum has a prototype of the CP that consists of a single type of ␣-and ␤-subunit, with all the ␤-subunits being catalytically active. Another difference between archaeal and eukaryotic CPs is the structure of the ␣-rings. Whereas archaeal CPs have a disordered gate that is permeable to peptide substrates, the eukaryotic ␣-ring of the CP is primarily in a closed state because the N termini of ␣1, ␣2, ␣3 (Pre9), ␣6, and ␣7 project into the opening of the ␣-ring (2-4). Therefore, the activity of the eukaryotic CP is basically latent. Of the ␣-subunits, ␣3 is supposed to be most important because the N terminus of ␣3 projects directly across the pseudo 7-fold symmetry axis. In addition, its deletion (␣3⌬N) causes disorder of the N termini of ␣1, ␣5, and ␣7, leading to an open state of ␣-rings (5). In vivo, binding of CP activators, such as the RPs, opens the closed ␣-ring (6, 7).The CP is assembled with the aid of various proteasome-dedicated chaperones in mammals and Saccharomyces cerevisiae (8-13). The assembly of CPs begins with the formation of the ␣-ring, assisted by the heterodimeric complexes PAC1-PAC2/Pba1-Pba2 and PAC3-PAC4/Pba3-Pba4 in mammals/yeast. After the formation of the ␣-...

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“…Though they lack HbYX motifs, the C-termini of 11S complexes insert into the same inter α-subunit pockets used by other activators (Forster et al 2005;Whitby et al 2000). In addition, PI31, originally identified as an inhibitor of CP in vitro (Chu-Ping et al 1992), represents a fourth class of CP regulator conserved from yeast to mammals (Bader et al 2011;Hatanaka et al 2011;Li et al 2014;Yashiroda et al 2015;Zaiss et al 2002). Phylogenomic analysis suggests that all four classes of regulator (RP, Blm10/PA200, 11S, and PI31) were present in the last eukaryotic common ancestor, despite the subsequent loss of some these proteins in many descendant lineages (Fort et al 2015).…”

Section: Assembly As a Regulatory Mechanism -Making Proteasomes For Tmentioning

confidence: 99%

Putting it all together: intrinsic and extrinsic mechanisms governing proteasome biogenesis

2017

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BACKGROUND:The 26S proteasome is at the heart of the ubiquitin-proteasome system, which is the key cellular pathway for the regulated degradation of proteins and enforcement of protein quality control. The 26S proteasome is an unusually large and complicated protease comprising a 28-subunit core particle (CP) capped by one or two 19-subunit regulatory particles (RP). Multiple activities within the RP process incoming ubiquitinated substrates for eventual degradation by the barrel-shaped CP. The large size and elaborate architecture of the proteasome have made it an exceptional model for understanding mechanistic themes in macromolecular assembly. OBJECTIVE:In the present work, we highlight the most recent mechanistic insights into proteasome assembly, with particular emphasis on intrinsic and extrinsic factors regulating proteasome biogenesis. We also describe new and exciting questions arising about how proteasome assembly is regulated and deregulated in normal and diseased cells. METHODS:A comprehensive literature search using the PubMed search engine was performed, and key findings yielding mechanistic insight into proteasome assembly were included in this review. RESULTS:Key recent studies have revealed that proteasome biogenesis is dependent upon intrinsic features of the subunits themselves as well as extrinsic factors, many of which function as dedicated chaperones. CONCLUSION:Cells rely on a diverse set of mechanistic strategies to ensure the rapid, efficient, and faithful assembly of proteasomes from their cognate subunits. Importantly, physiological as well as pathological changes to proteasome assembly are emerging as exciting paradigms to alter protein degradation in vivo.

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Fub1p, a novel protein isolated by boundary screening, binds the proteasome complex

Cited by 16 publications

References 53 publications

Proteasome Structure and Assembly

Proteasome Structure and Assembly

N-Terminal α7 Deletion of the Proteasome 20S Core Particle Substitutes for Yeast PI31 Function

Putting it all together: intrinsic and extrinsic mechanisms governing proteasome biogenesis

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