6eqi
From Proteopedia
Structure of PINK1 bound to ubiquitin
Structural highlights
Function[UBC_HUMAN] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.[1] [2] Publication Abstract from PubMedAutosomal recessive juvenile Parkinsonism (AR-JP) is caused by mutations in a number of PARK genes, in particular in the E3 ubiquitin ligase Parkin (PARK2), and in its upstream protein kinase PINK1 (PARK6). PINK1 phosphorylates ubiquitin and the Parkin ubiquitin-like domain on structurally protected Ser65 to trigger mitophagy. We here report a crystal structure of a nanobody-stabilised complex between Pediculus humanus corporis (Ph)PINK1 with ubiquitin in the 'C-terminally retracted' (Ub-CR) conformation. The structure reveals many peculiarities of PINK1, including the architecture of the C-terminal region, and reveals how the PINK1 N-lobe binds ubiquitin via a unique insertion. The flexible Ser65-loop in the Ub-CR conformation reaches the activation segment, facilitating placement of Ser65 in a phosphate accepting position. The structure further explains how autophosphorylation in the N-lobe stabilises structurally and functionally important insertions, and reveals the molecular basis for AR-JP causing mutations, some of which disrupt ubiquitin binding. Structure of PINK1 in complex with its substrate ubiquitin.,Schubert AF, Gladkova C, Pardon E, Wagstaff JL, Freund SMV, Steyaert J, Maslen SL, Komander D Nature. 2017 Oct 30. pii: nature24645. doi: 10.1038/nature24645. PMID:29160309[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Body louse | Camelus glama | Human | Non-specific serine/threonine protein kinase | Freund, S M.V | Gladkova, C | Komander, D | Maslen, S | Pardon, E | Schubert, A F | Steyaert, J | Wagstaff, J L | Pink1 ubiquitin mitophagy nanobody substrate recognition complex parkinson's disease | Transferase
