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Structure and Function of Adenomatous Polyposis Coli

Author: ZhangZhenYi
Tutor: WuGeng
School: Shanghai Jiaotong University
Course: Biochemistry and Molecular Biology
Keywords: Colon cancer APC Wnt signaling pathway Armadillo repeats domain Asef Amer1 Dlg1
CLC: R735.35
Type: PhD thesis
Year: 2012
Downloads: 75
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Abstract


Colon cancer is one of the leading causes of cancer deaths among adults in thewestern world. And the occurrence of this disease also increases quickly in China. Theinitial identification of the Adenomatous Polyposis Coli gene as a related gene of thecolon cancer was described very early. Muation of APC is the early event in FamilialAdenomatous Polyposis (FAP) and other colorectal cancers.Understanding the underlyingmolecular changes that produce colon cancer is critical for our ability to develop bettermethods to detect and treat this disease early. Because disruption of APC is common tomost of these tumors, the biology of APC is at the core of the problem. The firstrecognized function of APC was its role in Wnt signaling pathway. It acts as a Wntsignaling suppressor, promoting the degradation of β-catenin. In addition to its role in Wntsignaling pathway, APC was reported to participate may important cellular processes, suchas cell adhesion, cell migration, cell proliferation and chromosome stability. However,despite of the multitude of studies on the function of APC and its partners, only a fewstructural informations were available. The lack of the structural information of someimportant regions of APC and its partners has hindered our understanding of the molecularnature of APC and the mechanisms of its function. In order to settle these problems, wecarried out a systematic and extensive study on the structure and function of APC.The Armadillo repeats domain (ARM) is most conserved region of APC protein. Itprovides a structural platform for many interaction partners, including Asef, KAP3,IQGAP1, Amer1and PP2A-B56etc. And the functions of APC-ARM vary from genetranscription to cell migration and others. By continous attempts and efforts, we obtainedtwo crystal forms of APC-ARM domain at first. Then we solved their crystal structures. Inaddition to description of the structural information of this important domain, we also analyzed its inherited molecular nature and its ligand binding sites. Similar to the structureof β-catenin, the overall structure of APC-ARM is composed of seven armadillo repeatsforming a right handed superhelix, and a groove involved in recognition of its bindingpartners is generated by the super-helical twist of ARM domains. Furthermore,comparison of the structures of APC-ARM reveals its inherited flexibility.After deciphering the structure of APC-ARM domain, we tried to characterize therecognition mechanism of APC-ARM with its partners. Among the partners, the structureof Asef in complex with APC-ARM was firstly solved by us. After analysis, wecharacterized the recognition mechanism of APC-ARM and Asef, and then we alsoanalyzed the activation mechanism of APC/Asef complex, and proposed some hints forthis process. In addition, we found that the APC-ARM is actually composed of nine Armrepeats instead of seven, so we redefined the range of the APC-ARM domain.Furthermore, we focused on Amer1, another important partner of APC-ARM. It wasreported that Amer1contain three APC binding regions, and it can recruit the APC to theplasma membrane. However, the sizes of the reported binding regions are far beyond theAPC-ARM binding ability. So, on the basis of bioinformational analysis, the APC bindingregions of Amer1were further mapped by us. To date, the localizations of first two APCbinding sites, CA1and CA2, were successfully mapped, and then the structure ofAPC/CA1and APC/CA2complex were solved. However, due to the specific bindingmode of the third APC binding sites, we have not accomplished the work of mapping CA3yet. Analysis of the structures of APC/CA1and APC/CA2revealed that both of CA1andCA2recognized with APC in a way similar to Asef. We found that they shared aconsensus APC binding motif, which may be also present in other APC-ARM bindingproteins. Although the recognition mechanim of APC and Amer1was partly deciphered,there are still many work need to understand the precise mechanism of how APC/Amer1complex affect the cell adhesion.The C-terminal end of APC also plays important roles in its functions. Throughbinding with many parters, such as EB1and Dlg1, the C-terminal of APC is involved inthe regulation of cell migration and cell cycle. However, the molecular details of how EB1 and Dlg1recognize APC are not clear. In this study, we determined the crystal structuresof the PDZ1and PDZ2domains of Dlg1in complex with the C-terminal11residues ofAPC respectively, and performed biochemical and biophysical assays to investigate thespecific recognition mechanism of each PDZ domain. The results revealed that the β2/β3loops of PDZ1and PDZ2play important roles in binding with APC, through interactingwith the residues upstream of the canonical PDZ binding motif. Furthermore, theinteraction modes of APC and Dlg1can also explain the interation of APC and otherpartners of MAGUKs family, such as PSD-95and SAP102.In conclusion, in this paper, we performed an extenstively structural and functionalstudy of APC and its partners. The structures of APC-ARM domain and the complexes ofAPC/Asef, APC/Amer1and APC/Dlg1have been successfully solved and the relationshipsof their structures and functions have been well analyzed yet. These results will help us tobetter understand the biology of APC and provide important informations for the drugdesign and clinical research.

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CLC: > Medicine, health > Oncology > Gastrointestinal Cancer > Intestinal neoplasms > Colon tumor
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