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Structure of yeast Ape1 and its role in autophagic vesicle formation.

Su MY, Peng WH, Ho MR, Su SC, Chang YC, Chen GC, Chang CI
Autophagy 11 1580-93 (2015)
Cited: 12 times
EuropePMC logo PMID: 26208681

Abstract

In Saccharomyces cerevisiae, a constitutive biosynthetic transport pathway, termed the cytoplasm-to-vacuole targeting (Cvt) pathway, sequesters precursor aminopeptidase I (prApe1) dodecamers in the form of a large complex into a Cvt vesicle using autophagic machinery, targeting it into the vacuole (the yeast lysosome) where it is proteolytically processed into its mature form, Ape1, by removal of an amino-terminal 45-amino acid propeptide. prApe1 is thought to serve as a scaffolding cargo critical for the assembly of the Cvt vesicle by presenting the propeptide to mediate higher-ordered complex formation and autophagic receptor recognition. Here we report the X-ray crystal structure of Ape1 at 2.5 Å resolution and reveal its dodecameric architecture consisting of dimeric and trimeric units, which associate to form a large tetrahedron. The propeptide of prApe1 exhibits concentration-dependent oligomerization and forms a stable tetramer. Structure-based mutagenesis demonstrates that disruption of the inter-subunit interface prevents dodecameric assembly and vacuolar targeting in vivo despite the presence of the propeptide. Furthermore, by examining the vacuolar import of propeptide-fused exogenous protein assemblies with different quaternary structures, we found that 3-dimensional spatial distribution of propeptides presented by a scaffolding cargo is essential for the assembly of the Cvt vesicle for vacuolar delivery. This study describes a molecular framework for understanding the mechanism of Cvt or autophagosomal biogenesis in selective macroautophagy.

Reviews - 4r8f mentioned but not cited (1)

  1. Next-generation electron microscopy in autophagy research. Hurley JH, Nogales E. Curr Opin Struct Biol 41 211-216 (2016)

Articles - 4r8f mentioned but not cited (2)

  1. Higher-order assemblies of oligomeric cargo receptor complexes form the membrane scaffold of the Cvt vesicle. Bertipaglia C, Schneider S, Jakobi AJ, Tarafder AK, Bykov YS, Picco A, Kukulski W, Kosinski J, Hagen WJ, Ravichandran AC, Wilmanns M, Wilmanns M, Kaksonen M, Briggs JA, Sachse C. EMBO Rep 17 1044-1060 (2016)
  2. Structure of yeast Ape1 and its role in autophagic vesicle formation. Su MY, Peng WH, Ho MR, Su SC, Chang YC, Chen GC, Chang CI. Autophagy 11 1580-1593 (2015)


Reviews citing this publication (3)

  1. Mechanisms of Selective Autophagy. Zaffagnini G, Martens S. J Mol Biol 428 1714-1724 (2016)
  2. Structural Biology of the Cvt Pathway. Yamasaki A, Noda NN. J Mol Biol 429 531-542 (2017)
  3. Recent Advances in Single-Particle Electron Microscopic Analysis of Autophagy Degradation Machinery. Cheung YWS, Nam SE, Yip CK. Int J Mol Sci 21 E8051 (2020)

Articles citing this publication (6)

  1. Structural Basis for the Magnesium-Dependent Activation and Hexamerization of the Lon AAA+ Protease. Su SC, Lin CC, Tai HC, Chang MY, Ho MR, Babu CS, Liao JH, Wu SH, Chang YC, Lim C, Chang CI. Structure 24 676-686 (2016)
  2. Structural Basis for Receptor-Mediated Selective Autophagy of Aminopeptidase I Aggregates. Yamasaki A, Watanabe Y, Adachi W, Suzuki K, Matoba K, Kirisako H, Kumeta H, Nakatogawa H, Ohsumi Y, Inagaki F, Noda NN. Cell Rep 16 19-27 (2016)
  3. Molecular and structural mechanisms of ZZ domain-mediated cargo selection by Nbr1. Wang YY, Zhang J, Liu XM, Li Y, Sui J, Dong MQ, Ye K, Du LL. EMBO J 40 e107497 (2021)
  4. How metal cofactors drive dimer-dodecamer transition of the M42 aminopeptidase TmPep1050 of Thermotoga maritima. Dutoit R, Van Gompel T, Brandt N, Van Elder D, Van Dyck J, Sobott F, Droogmans L. J Biol Chem 294 17777-17789 (2019)
  5. Vps501, a novel vacuolar SNX-BAR protein cooperates with the SEA complex to regulate TORC1 signaling. Goyal S, Segarra VA, Nitika, Stetcher AM, Truman AW, Reitzel AM, Chi RJ. Traffic (2022)
  6. Improving therapeutic protein secretion in the probiotic yeast Saccharomyces boulardii using a multifactorial engineering approach. Durmusoglu D, Al'Abri I, Li Z, Islam Williams T, Collins LB, Martínez JL, Crook N. Microb Cell Fact 22 109 (2023)


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