Structure of Ubiquitin-fold Modifier 1-specific Protease UfSP2

Ha, Byung Hak; Jeon, Young Joo; Shin, Sang Chul; Tatsumi, Kanako; Komatsu, Masaaki; Tanaka, Keiji; Watson, Christopher M.; Wallis, Gillian A.; Chung, Chin Ha; Kim, Eunice EunKyeong

doi:10.1074/jbc.m110.172171

Cited by 51 publications

(83 citation statements)

References 34 publications

(30 reference statements)

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“…Lack of activity of the mutated protease is consistent with predictions made from the crystal structure of UFSP2 that the p.Tyr290 amino acid is a crucial residue within the UFSP2 active site. [15] In this in vitro assay, however, the mutated UFSP2 did not appear to exert a dominantnegative effect. Confirmation of the functional consequences of the BHD mutation on the Ufm1/UFSP2 pathway therefore requires further investigation.…”

Section: Discussionmentioning

confidence: 98%

Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia

et al. 2015

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Background. Beukes hip dysplasia (BHD) is an autosomal dominant disorder of variable penetrance that was originally identified in a large South African family of European origin. BHD is characterised by bilateral dysmorphism of the proximal femur, which results in severe degenerative osteoarthropathy. Previous studies mapped the disorder to a 3.34 Mb region on chromosome 4q35. Objective. To fine-map the BHD locus and identify the disease-causing mutation by direct sequencing. Results. The linked BHD allele was refined to 1.33 Mb, reducing the number of candidate genes from 25 to 16. Analysis of protein coding and invariant splice-site sequences in three distantly related individuals identified a single-candidate disease-causing variant c.868T>C within exon 8 of the ubiquitin-fold modifier 1 (Ufm1)-specific peptidase 2 gene, UFSP2. The presence of this unique mutation was confirmed in all 17 affected members of the BHD family who were genotyped. The mutation segregated with the BHD phenotype in the extended family with a two-point (single marker) LOD score of 10.4 (θ = 0.0 and 80% penetrance). The mutation predicts the substitution of a highly conserved amino acid, p.Tyr290His, in the encoded protein. In vitro functional assays performed using purified recombinant wild-type and mutant UFSP2 protein demonstrated that the BHD mutation abolishes UFSP2-mediated C-terminal cleavage of its substrate, Ufm1. Conclusion. We report a unique UFSP2 mutation that segregates with the BHD phenotype. The predicted amino acid substitution inactivates UFSP2 proteolytic function, thus implicating the ubiquitin-fold modifier 1 cascade in this form of severe hip osteoarthropathy. The facile polymerase chain reaction-based assay we describe could be used to confirm the diagnosis of BHD, or for presymptomatic testing of members of the extended BHD family.

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Section: Discussionmentioning

confidence: 98%

Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia

et al. 2015

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“…Solution structure studies have shown that Ufm1 adopts a similar ␤-grasp fold as seen in all other Ubls (12). Other studies have uncovered additional components in the Ufm1 conjugation or ufmylation pathway (13)(14)(15)(16)(17). Ufm1 is activated by an E1 enzyme identified as Uba5 and then is transferred to a conjugating enzyme (E2) Ufc1 (16,18).…”

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confidence: 99%

Mechanistic Study of Uba5 Enzyme and the Ufm1 Conjugation Pathway

Gavin

Hoar

et al. 2014

Journal of Biological Chemistry

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Background: Human ubiquitin-like protein Ufm1 and its activating enzyme, Uba5, are involved in endoplasmic reticulum (ER) stress response. Results: The Uba5-Ufm1 conjugation pathway is characterized in both reconstituted systems and cellular settings. Conclusion: Uba5 activates Ufm1 via a distinct two-step mechanism. Significance: This study represents the first mechanistic characterization of Uba5, a homodimeric member of the E1 enzyme family.

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“…Although the activity of murine UfSP1 was shown (14), it seems to be non-functional in other mammals, indicating that UfSP2 is the essential and conserved protease for the Ufm1 system.…”

Section: Discussionmentioning

confidence: 99%

“…Other studies clearly demonstrate a close association between the Ufm1 cascade and the endoplasmic reticulum (ER) (9,(12)(13)(14). The ER is responsible for synthesis and folding of secretory and membrane proteins.…”

mentioning

confidence: 99%

The Ubiquitin-fold Modifier 1 (Ufm1) Cascade of Caenorhabditis elegans

Hertel¹,

Daniel²,

Stegehake³

et al. 2013

Journal of Biological Chemistry

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Background:The novel ubiquitin-like modifier (UBL) Ufm1 has essential functions in mammalian embryonic development. Results: The Ufm1 cascade in Caenorhabditis elegans is required for normal growth and development and is involved in cellular stress response. Conclusions: The C. elegans Ufm1 cascade is an antagonist of the unfolded protein response. Significance: The C. elegans Ufm1 cascade offers a unique opportunity to understand the fundamentals underlining this UBL.

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Structure of Ubiquitin-fold Modifier 1-specific Protease UfSP2

Cited by 51 publications

References 34 publications

Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia

Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia

Mechanistic Study of Uba5 Enzyme and the Ufm1 Conjugation Pathway

The Ubiquitin-fold Modifier 1 (Ufm1) Cascade of Caenorhabditis elegans

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