Structural highlights
Structure
Parkin is composed of six different domains: IBR, RING1, RING2, RING0, REP, and UBI. Four of these domains contain zinc fingers that are common characteristics of the RBR family. The zinc finger found in UBI is unique to parkin. IBR contains one of these zinc fingers along with a hinge that connects to RING1, which allows for flexibility and function. RING1 contains an E2 binding site and is the only domain in parkin to contain a C3HC4 cross-brace zinc coordination topology, which is found in other RING fingers. RING2 is very similar to IBR but RING2 contains a catalytic site that coordinates two zinc atoms. RING2 also mediates the hydrophobic groove found in RING0. RING0 is composed of four subdomains that have interdomain interactions. RING0 is a zinc-binding fold that connects RING1 and RING2. It has extensive hydrophobic interactions with RING2. RING0 also has two zinc atoms that are coordinated by four zinc-binding loops. REP is composed of an alpha helix surrounded by unstructured regions that hold it together. It primarily serves as a linker between IBR and RING2. UBI is an ubiquitin-like domain with a 60 amino acid linker. The zinc finger found in UBI is unique to parkin.
Function
[PRKN2_RAT] Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins, such as BCL2, SYT11, CCNE1, GPR37, STUB1, a 22 kDa O-linked glycosylated isoform of SNCAIP, SEPT5, ZNF746 and AIMP2. Mediates monoubiquitination as well as 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context. Participates in the removal and/or detoxification of abnormally folded or damaged protein by mediating 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: 'Lys-63'-linked polyubiquitinated misfolded proteins are then recognized by HDAC6, leading to their recruitment to aggresomes, followed by degradation. Mediates 'Lys-63'-linked polyubiquitination of SNCAIP, possibly playing a role in Lewy-body formation. Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy. Promotes the autophagic degradation of dysfunctional depolarized mitochondria. Mediates 'Lys-48'-linked polyubiquitination of ZNF746, followed by degradation of ZNF746 by the proteasome; possibly playing a role in role in regulation of neuron death. Limits the production of reactive oxygen species (ROS). Loss of this ubiquitin ligase activity appears to be the mechanism underlying pathogenesis of PARK2. May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity. May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. Regulates cyclin-E during neuronal apoptosis. May represent a tumor suppressor gene (By similarity).
Publication Abstract from PubMed
Mutations in the Parkin gene are responsible for an autosomal recessive form of Parkinson's disease. The parkin protein is a RING-In-Between-RING (RBR) E3 ubiquitin ligase, which exhibits low basal activity. Here, we describe the crystal structure of full-length parkin. The structure shows parkin in an auto-inhibited state and provides insight into how it is activated. RING0 occludes the ubiquitin acceptor site Cys431 in RING2, whereas a repressor element of parkin (REP) binds RING1 and blocks its E2-binding site. Mutations that disrupted these inhibitory interactions activated parkin both in vitro and in cells. Parkin is neuroprotective and these findings may provide a structural and mechanistic framework for enhancing parkin activity.
Structure of Parkin Reveals Mechanisms for Ubiquitin Ligase Activation.,Trempe JF, Sauve V, Grenier K, Seirafi M, Tang MY, Menade M, Al-Abdul-Wahid S, Krett J, Wong K, Kozlov G, Nagar B, Fon EA, Gehring K Science. 2013 May 9. PMID:23661642[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Trempe JF, Sauve V, Grenier K, Seirafi M, Tang MY, Menade M, Al-Abdul-Wahid S, Krett J, Wong K, Kozlov G, Nagar B, Fon EA, Gehring K. Structure of Parkin Reveals Mechanisms for Ubiquitin Ligase Activation. Science. 2013 May 9. PMID:23661642 doi:10.1126/science.1237908
