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Structure of astrotactin-2: a conserved vertebrate-specific and perforin-like membrane protein involved in neuronal development.

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Ni T, Harlos K, Gilbert R
OpenAccess logo Open Biol 6 (2016)
Related entries: 5j67, 5j69

Cited: 21 times
EuropePMC logo PMID: 27249642

Abstract

The vertebrate-specific proteins astrotactin-1 and 2 (ASTN-1 and ASTN-2) are integral membrane perforin-like proteins known to play critical roles in neurodevelopment, while ASTN-2 has been linked to the planar cell polarity pathway in hair cells. Genetic variations associated with them are linked to a variety of neurodevelopmental disorders and other neurological pathologies, including an advanced onset of Alzheimer's disease. Here we present the structure of the majority endosomal region of ASTN-2, showing it to consist of a unique combination of polypeptide folds: a perforin-like domain, a minimal epidermal growth factor-like module, a unique form of fibronectin type III domain and an annexin-like domain. The perforin-like domain differs from that of other members of the membrane attack complex-perforin (MACPF) protein family in ways that suggest ASTN-2 does not form pores. Structural and biophysical data show that ASTN-2 (but not ASTN-1) binds inositol triphosphates, suggesting a mechanism for membrane recognition or secondary messenger regulation of its activity. The annexin-like domain is closest in fold to repeat three of human annexin V and similarly binds calcium, and yet shares no sequence homology with it. Overall, our structure provides the first atomic-resolution description of a MACPF protein involved in development, while highlighting distinctive features of ASTN-2 responsible for its activity.

Reviews citing this publication (5)

  1. Perforin-A key (shaped) weapon in the immunological arsenal. Spicer BA, Conroy PJ, Law RHP, Voskoboinik I, Whisstock JC. Semin Cell Dev Biol 72 117-123 (2017)
  2. Repurposing a pore: highly conserved perforin-like proteins with alternative mechanisms. Ni T, Gilbert RJC. Philos Trans R Soc Lond B Biol Sci 372 20160212 (2017)
  3. MACPF/CDC proteins in development: Insights from Drosophila torso-like. Johnson TK, Henstridge MA, Warr CG. Semin Cell Dev Biol 72 163-170 (2017)
  4. Neurodevelopmental MACPFs: The vertebrate astrotactins and BRINPs. Berkowicz SR, Giousoh A, Bird PI. Semin Cell Dev Biol 72 171-181 (2017)
  5. Cleave but not leave: Astrotactin proteins in development and disease. Chang H. IUBMB Life 69 572-577 (2017)

Articles citing this publication (16)

  1. The cryo-EM structure of the acid activatable pore-forming immune effector Macrophage-expressed gene 1. Pang SS, Bayly-Jones C, Radjainia M, Spicer BA, Law RHP, Hodel AW, Parsons ES, Ekkel SM, Conroy PJ, Ramm G, Venugopal H, Bird PI, Hoogenboom BW, Voskoboinik I, Gambin Y, Sierecki E, Dunstone MA, Whisstock JC. Nat Commun 10 4288 (2019)
  2. ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins. Behesti H, Fore TR, Wu P, Horn Z, Leppert M, Hull C, Hatten ME. Proc Natl Acad Sci U S A 115 E9717-E9726 (2018)
  3. Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity. Ni T, Jiao F, Yu X, Aden S, Ginger L, Williams SI, Bai F, Pražák V, Karia D, Stansfeld P, Zhang P, Munson G, Anderluh G, Scheuring S, Gilbert RJC. Sci Adv 6 eaax8286 (2020)
  4. Structural basis of soluble membrane attack complex packaging for clearance. Menny A, Lukassen MV, Couves EC, Franc V, Heck AJR, Bubeck D. Nat Commun 12 6086 (2021)
  5. Structures of monomeric and oligomeric forms of the Toxoplasma gondii perforin-like protein 1. Ni T, Williams SI, Rezelj S, Anderluh G, Harlos K, Stansfeld PJ, Gilbert RJC. Sci Adv 4 eaaq0762 (2018)
  6. Mining folded proteomes in the era of accurate structure prediction. Bayly-Jones C, Whisstock JC. PLoS Comput Biol 18 e1009930 (2022)
  7. Deep mixed model for marginal epistasis detection and population stratification correction in genome-wide association studies. Wang H, Yue T, Yang J, Wu W, Xing EP. BMC Bioinformatics 20 656 (2019)
  8. Intramembrane Proteolysis of Astrotactins. Chang H, Smallwood PM, Williams J, Nathans J. J Biol Chem 292 3506-3516 (2017)
  9. Deep Transcriptomic Analysis Reveals the Dynamic Developmental Progression during Early Development of Channel Catfish (Ictalurus punctatus). Ma X, Su B, Tian Y, Backenstose NJC, Ye Z, Moss A, Duong TY, Wang X, Dunham RA. Int J Mol Sci 21 E5535 (2020)
  10. Investigation of gene-gene interactions in cardiac traits and serum fatty acid levels in the LURIC Health Study. Zhou J, Passero K, Palmiero NE, Müller-Myhsok B, Kleber ME, Maerz W, Hall MA. PLoS One 15 e0238304 (2020)
  11. Murine astrotactins 1 and 2 have a similar membrane topology and mature via endoproteolytic cleavage catalyzed by a signal peptidase. Lara P, Tellgren-Roth Å, Behesti H, Horn Z, Schiller N, Enquist K, Cammenberg M, Liljenström A, Hatten ME, von Heijne G, Nilsson I. J Biol Chem 294 4538-4545 (2019)
  12. Genetic Variation in the ASTN2 Locus in Cardiovascular, Metabolic and Psychiatric Traits: Evidence for Pleiotropy Rather Than Shared Biology. Burt O, Johnston KJA, Graham N, Cullen B, Lyall DM, Lyall LM, Pell JP, Ward J, Smith DJ, Strawbridge RJ. Genes (Basel) 12 1194 (2021)
  13. A Case Study on the Keap1 Interaction with Peptide Sequence Epitopes Selected by the Peptidomic mRNA Display. Hirose H, Hideshima T, Katoh T, Suga H. Chembiochem 20 2089-2100 (2019)
  14. In Cerebellar Atrophy of 12-Month-Old ATM-Null Mice, Transcriptome Upregulations Concern Most Neurotransmission and Neuropeptide Pathways, While Downregulations Affect Prominently Itpr1, Usp2 and Non-Coding RNA. Reichlmeir M, Canet-Pons J, Koepf G, Nurieva W, Duecker RP, Doering C, Abell K, Key J, Stokes MP, Zielen S, Schubert R, Ivics Z, Auburger G. Cells 12 2399 (2023)
  15. Lung adenocarcinomas without driver genes converge to common adaptive strategies through diverse genetic, epigenetic, and niche construction evolutionary pathways. Gatenby RA, Luddy KA, Teer JK, Berglund A, Freischel AR, Carr RM, Lam AE, Pienta KJ, Amend SR, Austin RH, Hammarlund EU, Cleveland JL, Tsai KY, Brown JS. Med Oncol 41 135 (2024)
  16. Sea Anemone Membrane Attack Complex/Perforin Superfamily Demonstrates an Evolutionary Transitional State between Venomous and Developmental Functions. Surm JM, Landau M, Columbus-Shenkar YY, Moran Y. Mol Biol Evol 41 msae082 (2024)


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