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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.


Related in: MedlinePlus

A) Domain Structure of the Parkin Protein. The five major domains of Parkin are listed across the top and include the Ubiquitin-like domain (Ubl), RING0, as well as RING1, the In Between RING domain (IBR), and RING2 within the Ring IBR RING, (RBR) region. Listed under each zinc binding domain is the pattern of each zinc ion binding site, i.e. RING0 site I = 4 Cys residues (C4), RING0 site II = three Cys and one His residue (C3H), etc. And, finally, the number of amino acid residues in each domain is listed at the bottom. Note that the RING2 pattern of Cys and His zinc binding ligands, as well as the domain boundaries listed at the bottom are according to the Morett and Bork (1999) [104] selection of ligands and not those predicted by our new RING2 model. B) The spacing of Cys and His zinc ion ligands in RBR proteins according to an alignment comparison by Marin and Ferrus (2002) [14]. X indicates the number of amino acid residues between consecutive ligands in the primary protein sequence. C) The classical cross-brace structure shows the interleaved ligand arrangement for the two zinc binding sites and is found in many RING domains. RING1 of Parkin likely forms a cross brace structure with parkin C238=C1, C241=C2, C253=C3, H257, C260=C4, C263=C5, C289=C6, and C293=C7.
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Figure 1: A) Domain Structure of the Parkin Protein. The five major domains of Parkin are listed across the top and include the Ubiquitin-like domain (Ubl), RING0, as well as RING1, the In Between RING domain (IBR), and RING2 within the Ring IBR RING, (RBR) region. Listed under each zinc binding domain is the pattern of each zinc ion binding site, i.e. RING0 site I = 4 Cys residues (C4), RING0 site II = three Cys and one His residue (C3H), etc. And, finally, the number of amino acid residues in each domain is listed at the bottom. Note that the RING2 pattern of Cys and His zinc binding ligands, as well as the domain boundaries listed at the bottom are according to the Morett and Bork (1999) [104] selection of ligands and not those predicted by our new RING2 model. B) The spacing of Cys and His zinc ion ligands in RBR proteins according to an alignment comparison by Marin and Ferrus (2002) [14]. X indicates the number of amino acid residues between consecutive ligands in the primary protein sequence. C) The classical cross-brace structure shows the interleaved ligand arrangement for the two zinc binding sites and is found in many RING domains. RING1 of Parkin likely forms a cross brace structure with parkin C238=C1, C241=C2, C253=C3, H257, C260=C4, C263=C5, C289=C6, and C293=C7.

Mentions: Parkin belongs to the E3 ubiquitin ligase subset of the RBR protein family (reviewed in Eisenhaber et al. (2007) [11]. The primary domain structure of RBR ubiquitin ligases consists of three consecutive domains, each of approximately 50 amino acids: RING1, in between RING (IBR), and RING2. The Parkin RBR domain structure is shown in Fig. (1A). Historically, “RING”, an abbreviation for “Really Interesting New Gene”, was coined by Lovering et al. [12] and described a cysteine-rich motif. The combination of two linked RINGs in the same protein was first described by Van der Reijden (1999) [13] and eventually became known as the RBR. The RBR structure is apparently an ancient evolutionary feature that has endured for over a billion years [14]. Parkin orthologs, genes similar to Parkin because they originate from a common ancestor, can be found in vertebrates, insects and nematodes, but not in fungi or plants [14]. The amino acid residues, cysteine and histidine are interspersed among the RING amino acid sequences in a pattern that promotes binding of zinc ions. A sequence alignment comparison of RBR proteins revealed that the two RING domains in the RBR differed in spacing and number of conserved amino acid residues [14] (Fig. 1B). In general, RING1 is longer with more variability in spacing than RING2. The Parkin RINGs can be fit into this general sequence structure (Fig. 1A and B). RING1 holds two zinc ions in a cross brace arrangement with the first and second Cys pairing with the fourth and fifth Cys to hold one zinc ion (Fig. 1C). A second zinc ion is bound by the third Cys, the His, and paired with the sixth and seventh Cys, (reviewed in Borden (2000) [15] and Matthews and Sunde (2002) [16]).


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

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

A) Domain Structure of the Parkin Protein. The five major domains of Parkin are listed across the top and include the Ubiquitin-like domain (Ubl), RING0, as well as RING1, the In Between RING domain (IBR), and RING2 within the Ring IBR RING, (RBR) region. Listed under each zinc binding domain is the pattern of each zinc ion binding site, i.e. RING0 site I = 4 Cys residues (C4), RING0 site II = three Cys and one His residue (C3H), etc. And, finally, the number of amino acid residues in each domain is listed at the bottom. Note that the RING2 pattern of Cys and His zinc binding ligands, as well as the domain boundaries listed at the bottom are according to the Morett and Bork (1999) [104] selection of ligands and not those predicted by our new RING2 model. B) The spacing of Cys and His zinc ion ligands in RBR proteins according to an alignment comparison by Marin and Ferrus (2002) [14]. X indicates the number of amino acid residues between consecutive ligands in the primary protein sequence. C) The classical cross-brace structure shows the interleaved ligand arrangement for the two zinc binding sites and is found in many RING domains. RING1 of Parkin likely forms a cross brace structure with parkin C238=C1, C241=C2, C253=C3, H257, C260=C4, C263=C5, C289=C6, and C293=C7.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: A) Domain Structure of the Parkin Protein. The five major domains of Parkin are listed across the top and include the Ubiquitin-like domain (Ubl), RING0, as well as RING1, the In Between RING domain (IBR), and RING2 within the Ring IBR RING, (RBR) region. Listed under each zinc binding domain is the pattern of each zinc ion binding site, i.e. RING0 site I = 4 Cys residues (C4), RING0 site II = three Cys and one His residue (C3H), etc. And, finally, the number of amino acid residues in each domain is listed at the bottom. Note that the RING2 pattern of Cys and His zinc binding ligands, as well as the domain boundaries listed at the bottom are according to the Morett and Bork (1999) [104] selection of ligands and not those predicted by our new RING2 model. B) The spacing of Cys and His zinc ion ligands in RBR proteins according to an alignment comparison by Marin and Ferrus (2002) [14]. X indicates the number of amino acid residues between consecutive ligands in the primary protein sequence. C) The classical cross-brace structure shows the interleaved ligand arrangement for the two zinc binding sites and is found in many RING domains. RING1 of Parkin likely forms a cross brace structure with parkin C238=C1, C241=C2, C253=C3, H257, C260=C4, C263=C5, C289=C6, and C293=C7.
Mentions: Parkin belongs to the E3 ubiquitin ligase subset of the RBR protein family (reviewed in Eisenhaber et al. (2007) [11]. The primary domain structure of RBR ubiquitin ligases consists of three consecutive domains, each of approximately 50 amino acids: RING1, in between RING (IBR), and RING2. The Parkin RBR domain structure is shown in Fig. (1A). Historically, “RING”, an abbreviation for “Really Interesting New Gene”, was coined by Lovering et al. [12] and described a cysteine-rich motif. The combination of two linked RINGs in the same protein was first described by Van der Reijden (1999) [13] and eventually became known as the RBR. The RBR structure is apparently an ancient evolutionary feature that has endured for over a billion years [14]. Parkin orthologs, genes similar to Parkin because they originate from a common ancestor, can be found in vertebrates, insects and nematodes, but not in fungi or plants [14]. The amino acid residues, cysteine and histidine are interspersed among the RING amino acid sequences in a pattern that promotes binding of zinc ions. A sequence alignment comparison of RBR proteins revealed that the two RING domains in the RBR differed in spacing and number of conserved amino acid residues [14] (Fig. 1B). In general, RING1 is longer with more variability in spacing than RING2. The Parkin RINGs can be fit into this general sequence structure (Fig. 1A and B). RING1 holds two zinc ions in a cross brace arrangement with the first and second Cys pairing with the fourth and fifth Cys to hold one zinc ion (Fig. 1C). A second zinc ion is bound by the third Cys, the His, and paired with the sixth and seventh Cys, (reviewed in Borden (2000) [15] and Matthews and Sunde (2002) [16]).

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.


Related in: MedlinePlus