6w2h: Difference between revisions

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== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/RD23A_HUMAN RD23A_HUMAN]] Multiubiquitin chain receptor involved in modulation of proteasomal degradation. Binds to 'Lys-48'-linked polyubiquitin chains in a length-dependent manner and with a lower affinity to 'Lys-63'-linked polyubiquitin chains. Proposed to be capable to bind simultaneously to the 26S proteasome and to polyubiquitinated substrates and to deliver ubiquitinated proteins to the proteasome.<ref>PMID:9372924</ref> <ref>PMID:14621999</ref> <ref>PMID:12643283</ref> <ref>PMID:15321727</ref> <ref>PMID:20614012</ref>  Involved in nucleotide excision repair and is thought to be functional equivalent for RAD23B in global genome nucleotide excision repair (GG-NER) by association with XPC. In vitro, the XPC:RAD23A dimer has NER activity. Can stabilize XPC.<ref>PMID:9372924</ref> <ref>PMID:14621999</ref> <ref>PMID:12643283</ref> <ref>PMID:15321727</ref> <ref>PMID:20614012</ref>  Involved in vpr-dependent replication of HIV-1 in non-proliferating cells and primary macrophages. Required for the association of HIV-1 vpr with the host proteasome.<ref>PMID:9372924</ref> <ref>PMID:14621999</ref> <ref>PMID:12643283</ref> <ref>PMID:15321727</ref> <ref>PMID:20614012</ref>   
[[https://www.uniprot.org/uniprot/RD23A_HUMAN RD23A_HUMAN]] Multiubiquitin chain receptor involved in modulation of proteasomal degradation. Binds to 'Lys-48'-linked polyubiquitin chains in a length-dependent manner and with a lower affinity to 'Lys-63'-linked polyubiquitin chains. Proposed to be capable to bind simultaneously to the 26S proteasome and to polyubiquitinated substrates and to deliver ubiquitinated proteins to the proteasome.<ref>PMID:9372924</ref> <ref>PMID:14621999</ref> <ref>PMID:12643283</ref> <ref>PMID:15321727</ref> <ref>PMID:20614012</ref>  Involved in nucleotide excision repair and is thought to be functional equivalent for RAD23B in global genome nucleotide excision repair (GG-NER) by association with XPC. In vitro, the XPC:RAD23A dimer has NER activity. Can stabilize XPC.<ref>PMID:9372924</ref> <ref>PMID:14621999</ref> <ref>PMID:12643283</ref> <ref>PMID:15321727</ref> <ref>PMID:20614012</ref>  Involved in vpr-dependent replication of HIV-1 in non-proliferating cells and primary macrophages. Required for the association of HIV-1 vpr with the host proteasome.<ref>PMID:9372924</ref> <ref>PMID:14621999</ref> <ref>PMID:12643283</ref> <ref>PMID:15321727</ref> <ref>PMID:20614012</ref>   
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== Publication Abstract from PubMed ==
The structure of the first ubiquitin-associated domain from HHR23A, UBA(1), was determined by X-ray crystallography at a 1.60 A resolution, and its stability, folding kinetics, and residual structure under denaturing conditions have been investigated. The concentration dependence of thermal denaturation and size-exclusion chromatography indicate that UBA(1) is monomeric. Guanidine hydrochloride (GdnHCl) denaturation experiments reveal that the unfolding free energy, DeltaGu degrees '(H2O), of UBA(1) is 2.4 kcal mol(-1). Stopped-flow folding kinetics indicates sub-millisecond folding with only proline isomerization phases detectable at 25 degrees C. The full folding kinetics are observable at 4 degrees C, yielding a folding rate constant, kf, in the absence of a denaturant of 13,000 s(-1) and a Tanford beta-value of 0.80, consistent with a compact transition state. Evaluation of the secondary structure via circular dichroism shows that the residual helical structure in the denatured state is replaced by polyproline II structure as the GdnHCl concentration increases. Analysis of NMR secondary chemical shifts for backbone (15)NH, (13)CO, and (13)Calpha atoms between 4 and 7 M GdnHCl shows three islands of residual helical secondary structure that align in sequence with the three native-state helices. Extrapolation of the NMR data to 0 M GdnHCl demonstrates that helical structure would populate to 17-33% in the denatured state under folding conditions. Comparison with NMR data for a peptide corresponding to helix 1 indicates that this helix is stabilized by transient tertiary interactions in the denatured state of UBA(1). The high helical content in the denatured state, which is enhanced by transient tertiary interactions, suggests a diffusion-collision folding mechanism.
Residual Structure in the Denatured State of the Fast-Folding UBA(1) Domain from the Human DNA Excision Repair Protein HHR23A.,Becht DC, Leavens MJ, Zeng B, Rothfuss MT, Briknarova K, Bowler BE Biochemistry. 2022 May 3;61(9):767-784. doi: 10.1021/acs.biochem.2c00011. Epub, 2022 Apr 16. PMID:35430812<ref>PMID:35430812</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6w2h" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>

Revision as of 11:10, 25 May 2022

Crystal Structure of the Internal UBA Domain of HHR23ACrystal Structure of the Internal UBA Domain of HHR23A

Structural highlights

6w2h is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:RAD23A (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[RD23A_HUMAN] Multiubiquitin chain receptor involved in modulation of proteasomal degradation. Binds to 'Lys-48'-linked polyubiquitin chains in a length-dependent manner and with a lower affinity to 'Lys-63'-linked polyubiquitin chains. Proposed to be capable to bind simultaneously to the 26S proteasome and to polyubiquitinated substrates and to deliver ubiquitinated proteins to the proteasome.[1] [2] [3] [4] [5] Involved in nucleotide excision repair and is thought to be functional equivalent for RAD23B in global genome nucleotide excision repair (GG-NER) by association with XPC. In vitro, the XPC:RAD23A dimer has NER activity. Can stabilize XPC.[6] [7] [8] [9] [10] Involved in vpr-dependent replication of HIV-1 in non-proliferating cells and primary macrophages. Required for the association of HIV-1 vpr with the host proteasome.[11] [12] [13] [14] [15]

Publication Abstract from PubMed

The structure of the first ubiquitin-associated domain from HHR23A, UBA(1), was determined by X-ray crystallography at a 1.60 A resolution, and its stability, folding kinetics, and residual structure under denaturing conditions have been investigated. The concentration dependence of thermal denaturation and size-exclusion chromatography indicate that UBA(1) is monomeric. Guanidine hydrochloride (GdnHCl) denaturation experiments reveal that the unfolding free energy, DeltaGu degrees '(H2O), of UBA(1) is 2.4 kcal mol(-1). Stopped-flow folding kinetics indicates sub-millisecond folding with only proline isomerization phases detectable at 25 degrees C. The full folding kinetics are observable at 4 degrees C, yielding a folding rate constant, kf, in the absence of a denaturant of 13,000 s(-1) and a Tanford beta-value of 0.80, consistent with a compact transition state. Evaluation of the secondary structure via circular dichroism shows that the residual helical structure in the denatured state is replaced by polyproline II structure as the GdnHCl concentration increases. Analysis of NMR secondary chemical shifts for backbone (15)NH, (13)CO, and (13)Calpha atoms between 4 and 7 M GdnHCl shows three islands of residual helical secondary structure that align in sequence with the three native-state helices. Extrapolation of the NMR data to 0 M GdnHCl demonstrates that helical structure would populate to 17-33% in the denatured state under folding conditions. Comparison with NMR data for a peptide corresponding to helix 1 indicates that this helix is stabilized by transient tertiary interactions in the denatured state of UBA(1). The high helical content in the denatured state, which is enhanced by transient tertiary interactions, suggests a diffusion-collision folding mechanism.

Residual Structure in the Denatured State of the Fast-Folding UBA(1) Domain from the Human DNA Excision Repair Protein HHR23A.,Becht DC, Leavens MJ, Zeng B, Rothfuss MT, Briknarova K, Bowler BE Biochemistry. 2022 May 3;61(9):767-784. doi: 10.1021/acs.biochem.2c00011. Epub, 2022 Apr 16. PMID:35430812[16]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Sugasawa K, Ng JM, Masutani C, Maekawa T, Uchida A, van der Spek PJ, Eker AP, Rademakers S, Visser C, Aboussekhra A, Wood RD, Hanaoka F, Bootsma D, Hoeijmakers JH. Two human homologs of Rad23 are functionally interchangeable in complex formation and stimulation of XPC repair activity. Mol Cell Biol. 1997 Dec;17(12):6924-31. PMID:9372924
  2. ↑ Wang Q, Goh AM, Howley PM, Walters KJ. Ubiquitin recognition by the DNA repair protein hHR23a. Biochemistry. 2003 Nov 25;42(46):13529-35. PMID:14621999 doi:10.1021/bi035391j
  3. ↑ Raasi S, Pickart CM. Rad23 ubiquitin-associated domains (UBA) inhibit 26 S proteasome-catalyzed proteolysis by sequestering lysine 48-linked polyubiquitin chains. J Biol Chem. 2003 Mar 14;278(11):8951-9. PMID:12643283
  4. ↑ Raasi S, Orlov I, Fleming KG, Pickart CM. Binding of polyubiquitin chains to ubiquitin-associated (UBA) domains of HHR23A. J Mol Biol. 2004 Aug 27;341(5):1367-79. PMID:15321727 doi:10.1016/j.jmb.2004.06.057
  5. ↑ Li G, Elder RT, Dubrovsky L, Liang D, Pushkarsky T, Chiu K, Fan T, Sire J, Bukrinsky M, Zhao RY. HIV-1 replication through hHR23A-mediated interaction of Vpr with 26S proteasome. PLoS One. 2010 Jun 29;5(6):e11371. doi: 10.1371/journal.pone.0011371. PMID:20614012 doi:10.1371/journal.pone.0011371
  6. ↑ Sugasawa K, Ng JM, Masutani C, Maekawa T, Uchida A, van der Spek PJ, Eker AP, Rademakers S, Visser C, Aboussekhra A, Wood RD, Hanaoka F, Bootsma D, Hoeijmakers JH. Two human homologs of Rad23 are functionally interchangeable in complex formation and stimulation of XPC repair activity. Mol Cell Biol. 1997 Dec;17(12):6924-31. PMID:9372924
  7. ↑ Wang Q, Goh AM, Howley PM, Walters KJ. Ubiquitin recognition by the DNA repair protein hHR23a. Biochemistry. 2003 Nov 25;42(46):13529-35. PMID:14621999 doi:10.1021/bi035391j
  8. ↑ Raasi S, Pickart CM. Rad23 ubiquitin-associated domains (UBA) inhibit 26 S proteasome-catalyzed proteolysis by sequestering lysine 48-linked polyubiquitin chains. J Biol Chem. 2003 Mar 14;278(11):8951-9. PMID:12643283
  9. ↑ Raasi S, Orlov I, Fleming KG, Pickart CM. Binding of polyubiquitin chains to ubiquitin-associated (UBA) domains of HHR23A. J Mol Biol. 2004 Aug 27;341(5):1367-79. PMID:15321727 doi:10.1016/j.jmb.2004.06.057
  10. ↑ Li G, Elder RT, Dubrovsky L, Liang D, Pushkarsky T, Chiu K, Fan T, Sire J, Bukrinsky M, Zhao RY. HIV-1 replication through hHR23A-mediated interaction of Vpr with 26S proteasome. PLoS One. 2010 Jun 29;5(6):e11371. doi: 10.1371/journal.pone.0011371. PMID:20614012 doi:10.1371/journal.pone.0011371
  11. ↑ Sugasawa K, Ng JM, Masutani C, Maekawa T, Uchida A, van der Spek PJ, Eker AP, Rademakers S, Visser C, Aboussekhra A, Wood RD, Hanaoka F, Bootsma D, Hoeijmakers JH. Two human homologs of Rad23 are functionally interchangeable in complex formation and stimulation of XPC repair activity. Mol Cell Biol. 1997 Dec;17(12):6924-31. PMID:9372924
  12. ↑ Wang Q, Goh AM, Howley PM, Walters KJ. Ubiquitin recognition by the DNA repair protein hHR23a. Biochemistry. 2003 Nov 25;42(46):13529-35. PMID:14621999 doi:10.1021/bi035391j
  13. ↑ Raasi S, Pickart CM. Rad23 ubiquitin-associated domains (UBA) inhibit 26 S proteasome-catalyzed proteolysis by sequestering lysine 48-linked polyubiquitin chains. J Biol Chem. 2003 Mar 14;278(11):8951-9. PMID:12643283
  14. ↑ Raasi S, Orlov I, Fleming KG, Pickart CM. Binding of polyubiquitin chains to ubiquitin-associated (UBA) domains of HHR23A. J Mol Biol. 2004 Aug 27;341(5):1367-79. PMID:15321727 doi:10.1016/j.jmb.2004.06.057
  15. ↑ Li G, Elder RT, Dubrovsky L, Liang D, Pushkarsky T, Chiu K, Fan T, Sire J, Bukrinsky M, Zhao RY. HIV-1 replication through hHR23A-mediated interaction of Vpr with 26S proteasome. PLoS One. 2010 Jun 29;5(6):e11371. doi: 10.1371/journal.pone.0011371. PMID:20614012 doi:10.1371/journal.pone.0011371
  16. ↑ Becht DC, Leavens MJ, Zeng B, Rothfuss MT, Briknarova K, Bowler BE. Residual Structure in the Denatured State of the Fast-Folding UBA(1) Domain from the Human DNA Excision Repair Protein HHR23A. Biochemistry. 2022 May 3;61(9):767-784. doi: 10.1021/acs.biochem.2c00011. Epub, 2022 Apr 16. PMID:35430812 doi:http://dx.doi.org/10.1021/acs.biochem.2c00011

6w2h, resolution 1.60Å

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