| Structural highlights
Function
[UBB_HUMAN] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.[1] [2] [DDI1_YEAST] Acts as a linker between the 19S proteasome and polyubiquitinated proteins like the HO endonuclease and UFO1 via UBA domain interactions with ubiquitin for their subsequent degradation. Required for S-phase checkpoint control. Appears to act as negative regulator of constitutive exocytosis. May act at the level of secretory vesicle docking and fusion as a competitive inhibitor of SNARE assembly.[3] [4] [5] [6] [7] [8] [9]
Publication Abstract from PubMed
Ddi1 belongs to a family of shuttle proteins targeting polyubiquitinated substrates for proteasomal degradation. Unlike the other proteasomal shuttles, Rad23 and Dsk2, Ddi1 remains an enigma: its function is not fully understood and structural properties are poorly characterized. We determined the structure and binding properties of the ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains of Ddi1 from Saccharomyces cerevisiae. We found that while Ddi1UBA forms a characteristic UBA:ubiquitin complex, Ddi1UBL has entirely uncharacteristic binding preferences. Despite having a ubiquitin-like fold, Ddi1UBL does not interact with typical UBL receptors but unexpectedly binds ubiquitin, forming a unique interface mediated by hydrophobic contacts and by salt bridges between oppositely charged residues of Ddi1UBL and ubiquitin. In stark contrast to ubiquitin and other UBLs, the beta-sheet surface of Ddi1UBL is negatively charged and therefore is recognized in a completely different way. The dual functionality of Ddi1UBL, capable of binding both ubiquitin and proteasome, suggests an intriguing mechanism for Ddi1 as a proteasomal shuttle.
DNA-Damage-Inducible 1 Protein (Ddi1) Contains an Uncharacteristic Ubiquitin-like Domain that Binds Ubiquitin.,Nowicka U, Zhang D, Walker O, Krutauz D, Castaneda CA, Chaturvedi A, Chen TY, Reis N, Glickman MH, Fushman D Structure. 2015 Mar 3;23(3):542-57. doi: 10.1016/j.str.2015.01.010. Epub 2015 Feb, 19. PMID:25703377[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell. 2006 Mar 17;21(6):737-48. PMID:16543144 doi:S1097-2765(06)00120-1
- ↑ Komander D. The emerging complexity of protein ubiquitination. Biochem Soc Trans. 2009 Oct;37(Pt 5):937-53. doi: 10.1042/BST0370937. PMID:19754430 doi:10.1042/BST0370937
- ↑ Lustgarten V, Gerst JE. Yeast VSM1 encodes a v-SNARE binding protein that may act as a negative regulator of constitutive exocytosis. Mol Cell Biol. 1999 Jun;19(6):4480-94. PMID:10330187
- ↑ Clarke DJ, Mondesert G, Segal M, Bertolaet BL, Jensen S, Wolff M, Henze M, Reed SI. Dosage suppressors of pds1 implicate ubiquitin-associated domains in checkpoint control. Mol Cell Biol. 2001 Mar;21(6):1997-2007. PMID:11238935 doi:http://dx.doi.org/10.1128/MCB.21.6.1997-2007.2001
- ↑ Saeki Y, Saitoh A, Toh-e A, Yokosawa H. Ubiquitin-like proteins and Rpn10 play cooperative roles in ubiquitin-dependent proteolysis. Biochem Biophys Res Commun. 2002 May 10;293(3):986-92. PMID:12051757 doi:http://dx.doi.org/10.1016/S0006-291X(02)00340-6
- ↑ Marash M, Gerst JE. Phosphorylation of the autoinhibitory domain of the Sso t-SNAREs promotes binding of the Vsm1 SNARE regulator in yeast. Mol Biol Cell. 2003 Aug;14(8):3114-25. Epub 2003 May 3. PMID:12925750 doi:http://dx.doi.org/10.1091/mbc.E02-12-0804
- ↑ Kaplun L, Tzirkin R, Bakhrat A, Shabek N, Ivantsiv Y, Raveh D. The DNA damage-inducible UbL-UbA protein Ddi1 participates in Mec1-mediated degradation of Ho endonuclease. Mol Cell Biol. 2005 Jul;25(13):5355-62. PMID:15964793 doi:http://dx.doi.org/25/13/5355
- ↑ Diaz-Martinez LA, Kang Y, Walters KJ, Clarke DJ. Yeast UBL-UBA proteins have partially redundant functions in cell cycle control. Cell Div. 2006 Dec 4;1:28. PMID:17144915 doi:http://dx.doi.org/1747-1028-1-28
- ↑ Ivantsiv Y, Kaplun L, Tzirkin-Goldin R, Shabek N, Raveh D. Unique role for the UbL-UbA protein Ddi1 in turnover of SCFUfo1 complexes. Mol Cell Biol. 2006 Mar;26(5):1579-88. PMID:16478980 doi:http://dx.doi.org/26/5/1579
- ↑ Nowicka U, Zhang D, Walker O, Krutauz D, Castaneda CA, Chaturvedi A, Chen TY, Reis N, Glickman MH, Fushman D. DNA-Damage-Inducible 1 Protein (Ddi1) Contains an Uncharacteristic Ubiquitin-like Domain that Binds Ubiquitin. Structure. 2015 Mar 3;23(3):542-57. doi: 10.1016/j.str.2015.01.010. Epub 2015 Feb, 19. PMID:25703377 doi:http://dx.doi.org/10.1016/j.str.2015.01.010
|
