Structural and functional characterization of Rpn12 identifies residues required for Rpn10 proteasome incorporation

Boehringer, Jonas; Riedinger, Christiane; Paraskevopoulos, K. M.; Johnson, Eachan O. D.; Lowe, E.D.; Khoudian, Christina; Smith, Derek T.; Noble, M.E.M.; Gordon, Colin; Endicott, Jane

doi:10.1042/bj20120542

Cited by 24 publications

(27 citation statements)

References 50 publications

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“…The redefined position of Rpn12 by da Fonseca et al . was shown to be incorrect upon the crystallization of this subunit, whose atomic structure fit into the previously attributed density with high fidelity 7 . The ambiguity surrounding the precise locations of Rpn8 and Rpn11 disappeared with the most recent structural work by Beck et al ., which has solidified the architectural organization of the RP 19 .…”

Section: The Regulatory Particle At Subnanometer Resolutionsupporting

confidence: 59%

“…In order to fully describe the mechanisms that govern these observations, it is crucial to place them in a structural context. While atomic structures for several isolated RP subunits have been determined by NMR and crystallography 1–7 , all attempts to produce an atomic structure of the complete 19S RP by crystallographic methods have so far failed, likely due to the sheer size and inherent flexibility of this dynamic assembly.…”

Section: Introductionmentioning

confidence: 99%

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The proteasome under the microscope: the regulatory particle in focus

Lander

Martin

Nogales

2013

Current Opinion in Structural Biology

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Since first imaged by electron microscopy, much effort has been placed into determining the structure and mechanism of the 26S proteasome. While the proteolytic core is understood in atomic detail, how substrates are engaged and transported to this core remains elusive. Substrate delivery is accomplished by a 19-subunit regulatory particle that binds to ubiquitinated substrates, detaches ubiquitin tags, unfolds the substrate, and translocates it into the peptidase in an ATP-dependent fashion. Recently, several labs have determined subnanometer cryoEM structures of the 26S proteasome, shedding light on the architecture of the regulatory complex. We discuss the biological insights into substrate processing provided by these structures, and the technical hurdles ahead to achieve an atomic resolution structure of the 26 proteasome.

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Section: The Regulatory Particle At Subnanometer Resolutionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

The proteasome under the microscope: the regulatory particle in focus

Lander

Martin

Nogales

2013

Current Opinion in Structural Biology

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“…In particular, PSMD12 is positioned in close proximity to the PSMD14 (RPN11) subunit, 47 which is involved in the hydrolysis of ubiquitin chains from targeted substrates before degradation by the 26S proteasome. 48 As such, the activity of PSMD14 might be affected in subjects with a downregulation of PSMD12, thereby resulting in impaired breakdown of ubiquitin-protein conjugates, which would mechanically increase the levels of polyubiquitinated substrate proteins. Alternatively, the increased accumulation of ubiquitin-modified proteins in subject 1, who carries the p.Arg123* nonsense variant, might also reflect a decreased accessibility of these substrates to the 26S proteasome through decreased amounts of incorporated RPN10 and RPN13.…”

Section: Congenital Malformationsmentioning

confidence: 99%

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Küry¹,

Besnard²,

Ebstein³

et al. 2017

The American Journal of Human Genetics

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Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.Proteolysis by the ubiquitin-proteasome system (UPS) is a tightly regulated biological process in eukaryotic cells and is crucial for their homeostasis, signaling, and fate determination. 1-3 Proteins subjected to degradation are typically marked by polyubiquitin chains to be hydrolyzed in a precise, rapid, timely, and ATP-dependent manner by the 19S regulatory subunit of the 26S proteasome. 3-6 UPS-dependent degradation essentially contributes to proteostasis and plays a key role in neuronal development and function 7,8 by regulating synaptic plasticity, 9,10

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“…Structures from (6; 56) (pdb codes 3txm and 4b0z). These proteins closely resemble each other and serve as homology models for Rpn3, Rpn5, Rpn7, and Rpn9.…”

Section: Figurementioning

confidence: 99%

Structural Biology of the Proteasome

Kish-Trier

Hill

2013

Annu. Rev. Biophys.

196

185

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The proteasome refers to a collection of complexes centered on the 20S proteasome core particle, a complex of 28 subunits that houses proteolytic sites in its hollow interior. Proteasomes are found in eukaryotes, archaea, and some eubacteria, and their activity is critical for many cellular pathways. Important advances include inhibitor binding studies and the structure of the immunoproteasome, whose specificity is altered by incorporation of inducible catalytic subunits. The inherent repression of the 20S CP is relieved by the ATP-independent activators, 11S and Blm10/PA200, whose structures reveal principles of proteasome mechanism. The structure of the ATP-dependent 19S regulatory particle, which mediates degradation of polyubiquitylated proteins, is being revealed by a combination of crystal or NMR structures of individual subunits and electron microscopy reconstruction of the intact complex. Other recent structural advances inform about mechanisms of assembly and the role of conformational changes in the functional cycle.

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Structural and functional characterization of Rpn12 identifies residues required for Rpn10 proteasome incorporation

Cited by 24 publications

References 50 publications

The proteasome under the microscope: the regulatory particle in focus

The proteasome under the microscope: the regulatory particle in focus

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Structural Biology of the Proteasome

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