5d94

Publication Abstract from PubMed

FYCO1 (FYVE and coiled-coil protein 1) is a motor adaptor that binds to PI3P (phosphatidylinositol 3-phosphate), to Rab7 and to LC3 to mediate transport of late endosomes and autophagosomes along microtubules in the plus end direction. We have previously shown that FYCO1 binds to LC3B via a 19-amino acid sequence containing a putative core LIR motif. Here, we show that FYCO1 preferentially binds to LC3A and -B. By peptide array-based two dimensional mutational scans of the binding to LC3B, we found FYCO1 to contain a C-terminally extended LIR domain. We determined the crystal structure of a complex between a 13-amino acid LIR peptide from FYCO1 and LC3B at 1.53 A resolution. By combining the structural information with mutational analyses both the basis for the C-terminal extended LIR and the specificity for LC3A/B binding were revealed. FYCO1 contains a 9-amino acid long F-type LIR motif. In addition to the canonical aromatic residue at position 1 and the hydrophobic residue at position 3, an acidic residue and a hydrophobic residue at positions 8 and 9, respectively, are important for efficient binding to LC3B explaining the C-terminal extension. The specificity for binding to LC3A/B is due to the interaction between D1285 in FYCO1 and H57 in LC3B. To address the functional significance of the LIR motif of FYCO1 we generated FYCO1 knock out cells that subsequently were reconstituted with GFP-FYCO1 wild type (WT) and LIR mutant constructs. Our data show that FYCO1 requires a functional LIR motif to facilitate efficient maturation of autophagosomes under basal conditions whereas starvation-induced autophagy was unaffected.

FYCO1 Contains a C-terminally Extended, LC3A/B-preferring LC3-Interacting Region (LIR) Motif Required for Efficient Maturation of Autophagosomes During Basal Autophagy.,Olsvik HL, Lamark T, Takagi K, Bowitz Larsen K, Evjen G, Overvatn A, Mizushima T, Johansen T J Biol Chem. 2015 Oct 14. pii: jbc.M115.686915. PMID:26468287^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.