5an9 | pdb_00005an9
Mechanism of eIF6 release from the nascent 60S ribosomal subunit
Structural highlights
Disease[SBDS_HUMAN] Idiopathic aplastic anemia;Shwachman-Diamond syndrome. The disease is caused by mutations affecting the gene represented in this entry.[1] [2] Function[RLA0_DICDI] Ribosomal protein P0 is the functional equivalent of E.coli protein L10. [IF6_DICDI] Binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit to form the 80S initiation complex in the cytoplasm. May also be involved in ribosome biogenesis. [RL40_DICDI] 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-48-linked is involved in protein degradation via the proteasome. 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 (By similarity). 60S ribosomal protein L40: component of the 60S subunit of the ribosome. [RL3_DICDI] The L3 protein is a component of the large subunit of cytoplasmic ribosomes. [SBDS_HUMAN] Required for the assembly of mature ribosomes and ribosome biogenesis. Together with EFTUD1, triggers the GTP-dependent release of EIF6 from 60S pre-ribosomes in the cytoplasm, thereby activating ribosomes for translation competence by allowing 80S ribosome assembly and facilitating EIF6 recycling to the nucleus, where it is required for 60S rRNA processing and nuclear export. Required for normal levels of protein synthesis. May play a role in cellular stress resistance. May play a role in cellular response to DNA damage. May play a role in cell proliferation.[3] [4] [5] [6] Publication Abstract from PubMedSBDS protein (deficient in the inherited leukemia-predisposition disorder Shwachman-Diamond syndrome) and the GTPase EFL1 (an EF-G homolog) activate nascent 60S ribosomal subunits for translation by catalyzing eviction of the antiassociation factor eIF6 from nascent 60S ribosomal subunits. However, the mechanism is completely unknown. Here, we present cryo-EM structures of human SBDS and SBDS-EFL1 bound to Dictyostelium discoideum 60S ribosomal subunits with and without endogenous eIF6. SBDS assesses the integrity of the peptidyl (P) site, bridging uL16 (mutated in T-cell acute lymphoblastic leukemia) with uL11 at the P-stalk base and the sarcin-ricin loop. Upon EFL1 binding, SBDS is repositioned around helix 69, thus facilitating a conformational switch in EFL1 that displaces eIF6 by competing for an overlapping binding site on the 60S ribosomal subunit. Our data reveal the conserved mechanism of eIF6 release, which is corrupted in both inherited and sporadic leukemias. Mechanism of eIF6 release from the nascent 60S ribosomal subunit.,Weis F, Giudice E, Churcher M, Jin L, Hilcenko C, Wong CC, Traynor D, Kay RR, Warren AJ Nat Struct Mol Biol. 2015 Nov;22(11):914-9. doi: 10.1038/nsmb.3112. Epub 2015 Oct, 19. PMID:26479198[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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