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Structural basis for the recognition of Asef by adenomatous polyposis coli.

Zhang Z, Chen L, Gao L, Lin K, Zhu L, Lu Y, Shi X, Gao Y, Zhou J, Xu P, Zhang J, Wu G
Cell Res 22 372-86 (2012)
Related entries: 3nmx, 3nmz

Cited: 31 times
EuropePMC logo PMID: 21788986

Abstract

Adenomatous polyposis coli (APC) regulates cell-cell adhesion and cell migration through activating the APC-stimulated guanine nucleotide-exchange factor (GEF; Asef), which is usually autoinhibited through the binding between its Src homology 3 (SH3) and Dbl homology (DH) domains. The APC-activated Asef stimulates the small GTPase Cdc42, which leads to decreased cell-cell adherence and enhanced cell migration. In colorectal cancers, truncated APC constitutively activates Asef and promotes cancer cell migration and angiogenesis. Here, we report crystal structures of the human APC/Asef complex. We find that the armadillo repeat domain of APC uses a highly conserved surface groove to recognize the APC-binding region (ABR) of Asef, conformation of which changes dramatically upon binding to APC. Key residues on APC and Asef for the complex formation were mutated and their importance was demonstrated by binding and activity assays. Structural superimposition of the APC/Asef complex with autoinhibited Asef suggests that the binding between APC and Asef might create a steric clash between Asef-DH domain and APC, which possibly leads to a conformational change in Asef that stimulates its GEF activity. Our structures thus elucidate the molecular mechanism of Asef recognition by APC, as well as provide a potential target for pharmaceutical intervention against cancers.

Reviews - 3nmw mentioned but not cited (1)

  1. Advances and Insights of APC-Asef Inhibitors for Metastatic Colorectal Cancer Therapy. Yang X, Zhong J, Zhang Q, Feng L, Zheng Z, Zhang J, Lu S. Front Mol Biosci 8 662579 (2021)

Articles - 3nmw mentioned but not cited (6)

  1. Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution. Yan Z, Bai X, Yan C, Wu J, Li Z, Xie T, Peng W, Yin C, Li X, Scheres SHW, Shi Y, Yan N. Nature 517 50-55 (2015)
  2. Structural basis for the recognition of Asef by adenomatous polyposis coli. Zhang Z, Chen L, Gao L, Lin K, Zhu L, Lu Y, Shi X, Gao Y, Zhou J, Xu P, Zhang J, Wu G. Cell Res 22 372-386 (2012)
  3. Domain architecture of BAF250a reveals the ARID and ARM-repeat domains with implication in function and assembly of the BAF remodeling complex. Sandhya S, Maulik A, Giri M, Singh M. PLoS One 13 e0205267 (2018)
  4. Structures of the APC-ARM domain in complexes with discrete Amer1/WTX fragments reveal that it uses a consensus mode to recognize its binding partners. Zhang Z, Akyildiz S, Xiao Y, Gai Z, An Y, Behrens J, Wu G. Cell Discov 1 15016 (2015)
  5. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)
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  1. The emerging role of guanine nucleotide exchange factors in ALS and other neurodegenerative diseases. Droppelmann CA, Campos-Melo D, Volkening K, Strong MJ. Front Cell Neurosci 8 282 (2014)
  2. Adenomatous Polyposis Coli (APC) in cell migration. Fang X, Svitkina TM. Eur J Cell Biol 101 151228 (2022)
  3. The structural biology of canonical Wnt signalling. Agostino M, Pohl SÖ. Biochem Soc Trans 48 1765-1780 (2020)

Articles citing this publication (21)

  1. A conformational switch in collybistin determines the differentiation of inhibitory postsynapses. Soykan T, Schneeberger D, Tria G, Buechner C, Bader N, Svergun D, Tessmer I, Poulopoulos A, Papadopoulos T, Varoqueaux F, Schindelin H, Brose N. EMBO J 33 2113-2133 (2014)
  2. Peptidomimetic inhibitors of APC-Asef interaction block colorectal cancer migration. Jiang H, Deng R, Yang X, Shang J, Lu S, Zhao Y, Song K, Liu X, Zhang Q, Chen Y, Chinn YE, Wu G, Li J, Chen G, Yu J, Zhang J. Nat Chem Biol 13 994-1001 (2017)
  3. CDC42 inhibition suppresses progression of incipient intestinal tumors. Sakamori R, Yu S, Zhang X, Hoffman A, Sun J, Das S, Vedula P, Li G, Fu J, Walker F, Yang CS, Yi Z, Hsu W, Yu DH, Shen L, Rodriguez AJ, Taketo MM, Bonder EM, Verzi MP, Gao N. Cancer Res 74 5480-5492 (2014)
  4. Large extent of disorder in Adenomatous Polyposis Coli offers a strategy to guard Wnt signalling against point mutations. Minde DP, Radli M, Forneris F, Maurice MM, Rüdiger SG. PLoS One 8 e77257 (2013)
  5. Structural insight into the mutual recognition and regulation between Suppressor of Fused and Gli/Ci. Zhang Y, Fu L, Qi X, Zhang Z, Xia Y, Jia J, Jiang J, Zhao Y, Wu G. Nat Commun 4 2608 (2013)
  6. Self-association of the APC tumor suppressor is required for the assembly, stability, and activity of the Wnt signaling destruction complex. Kunttas-Tatli E, Roberts DM, McCartney BM. Mol Biol Cell 25 3424-3436 (2014)
  7. Branched actin networks are assembled on microtubules by adenomatous polyposis coli for targeted membrane protrusion. Efimova N, Yang C, Chia JX, Li N, Lengner CJ, Neufeld KL, Svitkina TM. J Cell Biol 219 e202003091 (2020)
  8. Structural mechanism for the arginine sensing and regulation of CASTOR1 in the mTORC1 signaling pathway. Gai Z, Wang Q, Yang C, Wang L, Deng W, Wu G. Cell Discov 2 16051 (2016)
  9. Structure of the TBC1D7-TSC1 complex reveals that TBC1D7 stabilizes dimerization of the TSC1 C-terminal coiled coil region. Gai Z, Chu W, Deng W, Li W, Li H, He A, Nellist M, Wu G. J Mol Cell Biol 8 411-425 (2016)
  10. Ubiquitylation and degradation of adenomatous polyposis coli by MKRN1 enhances Wnt/β-catenin signaling. Lee HK, Lee EW, Seo J, Jeong M, Lee SH, Kim SY, Jho EH, Choi CH, Chung JY, Song J. Oncogene 37 4273-4286 (2018)
  11. Tumorigenic fragments of APC cause dominant defects in directional cell migration in multiple model systems. Nelson SA, Li Z, Newton IP, Fraser D, Milne RE, Martin DM, Schiffmann D, Yang X, Dormann D, Weijer CJ, Appleton PL, Näthke IS. Dis Model Mech 5 940-947 (2012)
  12. Genome-wide Analysis Reveals DNA Methylation Alterations in Obesity Associated with High Risk of Colorectal Cancer. Dong L, Ma L, Ma GH, Ren H. Sci Rep 9 5100 (2019)
  13. Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors. He X, Huang N, Qiu Y, Zhang J, Liu Y, Yin XL, Lu S. Molecules 26 962 (2021)
  14. Double inhibition and activation mechanisms of Ephexin family RhoGEFs. Zhang M, Lin L, Wang C, Zhu J. Proc Natl Acad Sci U S A 118 e2024465118 (2021)
  15. Truncated Adenomatous Polyposis Coli Mutation Induces Asef-Activated Golgi Fragmentation. Kim SB, Zhang L, Yoon J, Lee J, Min J, Li W, Grishin NV, Moon YA, Wright WE, Shay JW. Mol Cell Biol 38 e00135-18 (2018)
  16. Phosphorylation of serine 106 in Asef2 regulates cell migration and adhesion turnover. Evans JC, Hines KM, Forsythe JG, Erdogan B, Shi M, Hill S, Rose KL, McLean JA, Webb DJ. J Proteome Res 13 3303-3313 (2014)
  17. Rational design of a sensitivity-enhanced tracer for discovering efficient APC-Asef inhibitors. Zhong J, Guo Y, Lu S, Song K, Wang Y, Feng L, Zheng Z, Zhang Q, Wei J, Sang P, Shi Y, Cai J, Chen G, Liu CY, Yang X, Zhang J. Nat Commun 13 4961 (2022)
  18. APC Splicing Mutations Leading to In-Frame Exon 12 or Exon 13 Skipping Are Rare Events in FAP Pathogenesis and Define the Clinical Outcome. Disciglio V, Forte G, Fasano C, Sanese P, Lepore Signorile M, De Marco K, Grossi V, Cariola F, Simone C. Genes (Basel) 12 353 (2021)
  19. An APC Mutation in a Large Chinese Kindred With Familial Adenomatous Polyposis Was Identified Using Both Next Generation Sequencing and Simple STR Marker Haplotypes. Zhan Q, Wang L, Xu X, Sun Y, Li L, Qi X, Qi X, Chen F, Wei X, Raff ML, Yu P, Jin F. Front Genet 11 191 (2020)
  20. Computer-aided molecular design and optimization of potent inhibitors disrupting APC‒Asef interaction. Wang X, Du Z, Guo Y, Zhong J, Song K, Wang J, Yu J, Yang X, Liu CY, Shi T, Zhang J. Acta Pharm Sin B 14 2631-2645 (2024)
  21. From tumor mutational burden to characteristic targets analysis: Identifying the predictive biomarkers and natural product interventions in cancer management. Liu C, Yu Y, Wang G, Liu J, Liu R, Liu L, Yang X, Li H, Gao C, Lu Y, Zhuang J. Front Nutr 9 989989 (2022)


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