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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) The previous RING2 model based on the Morett and Bork (1999) selection of ligands [104]. The last four Cys ligands are constrained in their ability to form a zinc ion binding site and it was suggested that Parkin RING2 had only one bound zinc ion. However, experimental evidence suggested that Parkin RING2 binds two zinc ions [19]. B) Our newly predicted structural model explains how two zinc ions may be bound by RING2. C) Our predicted model for the RING2 domain with ligand residues in the zinc binding sites shown in orange (first binding site) and yellow (second binding site).
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Figure 4: A) The previous RING2 model based on the Morett and Bork (1999) selection of ligands [104]. The last four Cys ligands are constrained in their ability to form a zinc ion binding site and it was suggested that Parkin RING2 had only one bound zinc ion. However, experimental evidence suggested that Parkin RING2 binds two zinc ions [19]. B) Our newly predicted structural model explains how two zinc ions may be bound by RING2. C) Our predicted model for the RING2 domain with ligand residues in the zinc binding sites shown in orange (first binding site) and yellow (second binding site).

Mentions: A current model for RING2 structure is based on zinc ion ligand residues C418, C421, C431, H433, C436, C441, and C449 identified by Morett and Bork (1999) [104]. The model fits the classical ligand spacing [12, 102, 103, 105] (Fig. 2B), however spatial limitations prevent it from easily fitting into a cross-brace structure (Fig. 1C). In the Morett and Bork model, C418, C421, C431, H433 coordinate to the first zinc ion, but Capilli et al. (2004) showed that the RING2 domain of HHARI, a protein that shares both the RBR domain structure and the E3 ligase function of RING2 with Parkin, did not form a cross brace structure and binds only one zinc ion [18]. By analogy it was suggested that the RING2 domain of Parkin may also bind just one zinc atom (Fig. 4A). However, this contrasts with the zinc titration analysis that suggested that Parkin can bind a total of eight zinc ions, two each for RING0, RING1, IBR, and RING2 [19].


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

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

A) The previous RING2 model based on the Morett and Bork (1999) selection of ligands [104]. The last four Cys ligands are constrained in their ability to form a zinc ion binding site and it was suggested that Parkin RING2 had only one bound zinc ion. However, experimental evidence suggested that Parkin RING2 binds two zinc ions [19]. B) Our newly predicted structural model explains how two zinc ions may be bound by RING2. C) Our predicted model for the RING2 domain with ligand residues in the zinc binding sites shown in orange (first binding site) and yellow (second binding site).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: A) The previous RING2 model based on the Morett and Bork (1999) selection of ligands [104]. The last four Cys ligands are constrained in their ability to form a zinc ion binding site and it was suggested that Parkin RING2 had only one bound zinc ion. However, experimental evidence suggested that Parkin RING2 binds two zinc ions [19]. B) Our newly predicted structural model explains how two zinc ions may be bound by RING2. C) Our predicted model for the RING2 domain with ligand residues in the zinc binding sites shown in orange (first binding site) and yellow (second binding site).
Mentions: A current model for RING2 structure is based on zinc ion ligand residues C418, C421, C431, H433, C436, C441, and C449 identified by Morett and Bork (1999) [104]. The model fits the classical ligand spacing [12, 102, 103, 105] (Fig. 2B), however spatial limitations prevent it from easily fitting into a cross-brace structure (Fig. 1C). In the Morett and Bork model, C418, C421, C431, H433 coordinate to the first zinc ion, but Capilli et al. (2004) showed that the RING2 domain of HHARI, a protein that shares both the RBR domain structure and the E3 ligase function of RING2 with Parkin, did not form a cross brace structure and binds only one zinc ion [18]. By analogy it was suggested that the RING2 domain of Parkin may also bind just one zinc atom (Fig. 4A). However, this contrasts with the zinc titration analysis that suggested that Parkin can bind a total of eight zinc ions, two each for RING0, RING1, IBR, and RING2 [19].

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.