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Parkin, A Top Level Manager in the Cell's Sanitation Department.

Rankin CA, Roy A, Zhang Y, Richter M - Open Biochem J (2011)

Bottom Line: Some functions, such as participation in a multi-protein complex implicated in NMDA activity at the post synaptic density, do not require ubiquitination of substrate molecules.We have modeled the three RING domains of Parkin and have identified a new set of RING2 ligands.This set allows for binding of two rather than just one zinc ion, opening the possibility that the number of zinc ions bound acts as a molecular switch to modulate Parkin function.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biosciences Department, University of Kansas, Lawrence KS 66045, USA.

ABSTRACT
Parkin belongs to a class of multiple RING domain proteins designated as RBR (RING, in between RING, RING) proteins. In this review we examine what is known regarding the structure/function relationship of the Parkin protein. Parkin contains three RING domains plus a ubiquitin-like domain and an in-between-RING (IBR) domain. RING domains are rich in cysteine amino acids that act as ligands to bind zinc ions. RING domains may interact with DNA or with other proteins and perform a wide range of functions. Some function as E3 ubiquitin ligases, participating in attachment of ubiquitin chains to signal proteasome degradation; however, ubiquitin may be attached for purposes other than proteasome degradation. It was determined that the C-terminal most RING, RING2, is essential for Parkin to function as an E3 ubiquitin ligase and a number of substrates have been identified. However, Parkin also participates in a number of other fiunctions, such as DNA repair, microtubule stabilization, and formation of aggresomes. Some functions, such as participation in a multi-protein complex implicated in NMDA activity at the post synaptic density, do not require ubiquitination of substrate molecules. Recent observations of RING proteins suggest their function may be regulated by zinc ion binding. We have modeled the three RING domains of Parkin and have identified a new set of RING2 ligands. This set allows for binding of two rather than just one zinc ion, opening the possibility that the number of zinc ions bound acts as a molecular switch to modulate Parkin function.

No MeSH data available.


A) Our predicted structural model of the RING0 domain. The ligand residues shown in yellow (C150, C154, C212, and H215) represent the first zinc ion binding site; those in orange (C166, C169, C196, C201), the second binding site. B) A line drawing of our predicted structure shows the two interleaved zinc ion binding sites. Ligands one and two pair with seven and eight to form the first zinc binding site and the four internal Cys residues form the second zinc site. This is different than the RING0 structure predicted by Hristova et al. [19] where the first four Cys ligands form the first zinc site and the last three Cys plus the His residue form the second zinc binding site.
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Figure 3: A) Our predicted structural model of the RING0 domain. The ligand residues shown in yellow (C150, C154, C212, and H215) represent the first zinc ion binding site; those in orange (C166, C169, C196, C201), the second binding site. B) A line drawing of our predicted structure shows the two interleaved zinc ion binding sites. Ligands one and two pair with seven and eight to form the first zinc binding site and the four internal Cys residues form the second zinc site. This is different than the RING0 structure predicted by Hristova et al. [19] where the first four Cys ligands form the first zinc site and the last three Cys plus the His residue form the second zinc binding site.

Mentions: The overall topology of the predicted model for RING0 (Fig. 3A and B) is based on the DNAJ/hsp40 homology and differs from that proposed by Hristova et al. (2009) [19] in that the two zinc binding sites are interleaved, with a V-shaped extended β-hairpin topology in the linker region, similar to the cysteine rich domain of DNAJ. The long linker apparently does not impair binding of zinc ligands. The rest of the domain contains only a limited amount of regular secondary structure. The first binding site consists of Ligands one (Cys 150), two (Cys 154), seven (C212) and eight (H215), while the second is composed of Ligands 3-6 (C166, C169, C196, and C201). While the predicted model requires experimental validation, it provides the first plausible three dimensional model for zinc binding in RING0.


Parkin, A Top Level Manager in the Cell's Sanitation Department.

Rankin CA, Roy A, Zhang Y, Richter M - Open Biochem J (2011)

A) Our predicted structural model of the RING0 domain. The ligand residues shown in yellow (C150, C154, C212, and H215) represent the first zinc ion binding site; those in orange (C166, C169, C196, C201), the second binding site. B) A line drawing of our predicted structure shows the two interleaved zinc ion binding sites. Ligands one and two pair with seven and eight to form the first zinc binding site and the four internal Cys residues form the second zinc site. This is different than the RING0 structure predicted by Hristova et al. [19] where the first four Cys ligands form the first zinc site and the last three Cys plus the His residue form the second zinc binding site.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3104551&req=5

Figure 3: A) Our predicted structural model of the RING0 domain. The ligand residues shown in yellow (C150, C154, C212, and H215) represent the first zinc ion binding site; those in orange (C166, C169, C196, C201), the second binding site. B) A line drawing of our predicted structure shows the two interleaved zinc ion binding sites. Ligands one and two pair with seven and eight to form the first zinc binding site and the four internal Cys residues form the second zinc site. This is different than the RING0 structure predicted by Hristova et al. [19] where the first four Cys ligands form the first zinc site and the last three Cys plus the His residue form the second zinc binding site.
Mentions: The overall topology of the predicted model for RING0 (Fig. 3A and B) is based on the DNAJ/hsp40 homology and differs from that proposed by Hristova et al. (2009) [19] in that the two zinc binding sites are interleaved, with a V-shaped extended β-hairpin topology in the linker region, similar to the cysteine rich domain of DNAJ. The long linker apparently does not impair binding of zinc ligands. The rest of the domain contains only a limited amount of regular secondary structure. The first binding site consists of Ligands one (Cys 150), two (Cys 154), seven (C212) and eight (H215), while the second is composed of Ligands 3-6 (C166, C169, C196, and C201). While the predicted model requires experimental validation, it provides the first plausible three dimensional model for zinc binding in RING0.

Bottom Line: Some functions, such as participation in a multi-protein complex implicated in NMDA activity at the post synaptic density, do not require ubiquitination of substrate molecules.We have modeled the three RING domains of Parkin and have identified a new set of RING2 ligands.This set allows for binding of two rather than just one zinc ion, opening the possibility that the number of zinc ions bound acts as a molecular switch to modulate Parkin function.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biosciences Department, University of Kansas, Lawrence KS 66045, USA.

ABSTRACT
Parkin belongs to a class of multiple RING domain proteins designated as RBR (RING, in between RING, RING) proteins. In this review we examine what is known regarding the structure/function relationship of the Parkin protein. Parkin contains three RING domains plus a ubiquitin-like domain and an in-between-RING (IBR) domain. RING domains are rich in cysteine amino acids that act as ligands to bind zinc ions. RING domains may interact with DNA or with other proteins and perform a wide range of functions. Some function as E3 ubiquitin ligases, participating in attachment of ubiquitin chains to signal proteasome degradation; however, ubiquitin may be attached for purposes other than proteasome degradation. It was determined that the C-terminal most RING, RING2, is essential for Parkin to function as an E3 ubiquitin ligase and a number of substrates have been identified. However, Parkin also participates in a number of other fiunctions, such as DNA repair, microtubule stabilization, and formation of aggresomes. Some functions, such as participation in a multi-protein complex implicated in NMDA activity at the post synaptic density, do not require ubiquitination of substrate molecules. Recent observations of RING proteins suggest their function may be regulated by zinc ion binding. We have modeled the three RING domains of Parkin and have identified a new set of RING2 ligands. This set allows for binding of two rather than just one zinc ion, opening the possibility that the number of zinc ions bound acts as a molecular switch to modulate Parkin function.

No MeSH data available.