Limits...
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.


The predicted model of the RING1 domain using the I-TASSER algorithm. The model has a typical cross-brace structure and is in agreement with the previously suggested structure for Parkin RING1. The template identification was conducted using LOMETS, a metathreading server appoach with 9 third-party threading programs installed locally [111]. Multiple templates were collected from the topranking alignments in each of the 9 individual programs in LOMETS. A composite force field, consisting of the inherent knowledge-based potential and the spatial restraints collected from the multiple template structures, is then used for guiding the fragment assembly Monte Carlo simulations. The final models were selected based on the frequency of occurrence of the conformation appearing during the I-TASSER reassembly simulations (or the cluster size), identified by SPICKER [112]. Finally, full-atomic models are built by REMO [113] by optimizing the hydrogen-bonding network. B) The spacing of zinc site ligands in RING and LIM structures as described by Lovering et al. [12] and Freemont [103]. The ligands are numbered from one to eight in the top row and the intervening amino acid residues are depicted as “X”. The ligand spacing and location of the His residue is nearly the same in the two RING descriptions. The LIM structure is different in ligand spacing and also in location of the His residue.
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Figure 2: The predicted model of the RING1 domain using the I-TASSER algorithm. The model has a typical cross-brace structure and is in agreement with the previously suggested structure for Parkin RING1. The template identification was conducted using LOMETS, a metathreading server appoach with 9 third-party threading programs installed locally [111]. Multiple templates were collected from the topranking alignments in each of the 9 individual programs in LOMETS. A composite force field, consisting of the inherent knowledge-based potential and the spatial restraints collected from the multiple template structures, is then used for guiding the fragment assembly Monte Carlo simulations. The final models were selected based on the frequency of occurrence of the conformation appearing during the I-TASSER reassembly simulations (or the cluster size), identified by SPICKER [112]. Finally, full-atomic models are built by REMO [113] by optimizing the hydrogen-bonding network. B) The spacing of zinc site ligands in RING and LIM structures as described by Lovering et al. [12] and Freemont [103]. The ligands are numbered from one to eight in the top row and the intervening amino acid residues are depicted as “X”. The ligand spacing and location of the His residue is nearly the same in the two RING descriptions. The LIM structure is different in ligand spacing and also in location of the His residue.

Mentions: The fold of RING1 closely matches the RING finger domain of human UbcM4-interacting protein (PDB: 1WIM). The predicted structure of the RING1 domain (Fig. 2A) and the threading alignment with the identified template, suggest that RING1 adopts the classical zinc ligand spacing [12, 102, 103] (Fig. 1B, 2B) and assumes a typical cross brace structure (Fig. 1C) with residues C238, C241, C260 and C263 as ligands in the first zinc co-ordination site and C253, H257, C289 and C293 present in the second site.


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

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

The predicted model of the RING1 domain using the I-TASSER algorithm. The model has a typical cross-brace structure and is in agreement with the previously suggested structure for Parkin RING1. The template identification was conducted using LOMETS, a metathreading server appoach with 9 third-party threading programs installed locally [111]. Multiple templates were collected from the topranking alignments in each of the 9 individual programs in LOMETS. A composite force field, consisting of the inherent knowledge-based potential and the spatial restraints collected from the multiple template structures, is then used for guiding the fragment assembly Monte Carlo simulations. The final models were selected based on the frequency of occurrence of the conformation appearing during the I-TASSER reassembly simulations (or the cluster size), identified by SPICKER [112]. Finally, full-atomic models are built by REMO [113] by optimizing the hydrogen-bonding network. B) The spacing of zinc site ligands in RING and LIM structures as described by Lovering et al. [12] and Freemont [103]. The ligands are numbered from one to eight in the top row and the intervening amino acid residues are depicted as “X”. The ligand spacing and location of the His residue is nearly the same in the two RING descriptions. The LIM structure is different in ligand spacing and also in location of the His residue.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: The predicted model of the RING1 domain using the I-TASSER algorithm. The model has a typical cross-brace structure and is in agreement with the previously suggested structure for Parkin RING1. The template identification was conducted using LOMETS, a metathreading server appoach with 9 third-party threading programs installed locally [111]. Multiple templates were collected from the topranking alignments in each of the 9 individual programs in LOMETS. A composite force field, consisting of the inherent knowledge-based potential and the spatial restraints collected from the multiple template structures, is then used for guiding the fragment assembly Monte Carlo simulations. The final models were selected based on the frequency of occurrence of the conformation appearing during the I-TASSER reassembly simulations (or the cluster size), identified by SPICKER [112]. Finally, full-atomic models are built by REMO [113] by optimizing the hydrogen-bonding network. B) The spacing of zinc site ligands in RING and LIM structures as described by Lovering et al. [12] and Freemont [103]. The ligands are numbered from one to eight in the top row and the intervening amino acid residues are depicted as “X”. The ligand spacing and location of the His residue is nearly the same in the two RING descriptions. The LIM structure is different in ligand spacing and also in location of the His residue.
Mentions: The fold of RING1 closely matches the RING finger domain of human UbcM4-interacting protein (PDB: 1WIM). The predicted structure of the RING1 domain (Fig. 2A) and the threading alignment with the identified template, suggest that RING1 adopts the classical zinc ligand spacing [12, 102, 103] (Fig. 1B, 2B) and assumes a typical cross brace structure (Fig. 1C) with residues C238, C241, C260 and C263 as ligands in the first zinc co-ordination site and C253, H257, C289 and C293 present in the second site.

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.