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This dissertation, Structural and Functional Studies of Human APPL1-APPL2 BAR-PH Heterodimer, APPL2 BAR-PH Homodimer, and Lanthionine Synthetase Component C-like Protein 2 by Yujie, Chen, 陈宇杰, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: APPL BAR-PH heterodimer and APPL2 BAR-PH homodimerThe APPL (Adaptor protein containing PH domain, PTB domain and Leucine zipper) family are adaptor proteins with only two isoforms, APPL1 and APPL2. They bind to early endosomes with a small GTPase, Rab5, and mediate the interactions between various receptors and downstream signaling components, thus functioning in many signaling pathways evoked by adiponectin, insulin, FSH, EGF, and so on. However, evidences have shown APPL1 and APPL2 should perform some opposite functions, which cannot be simply explained by the functional differences attributed to their PTB domains. We hypothesize that the heterodimerization of APPL1 and APPL2's BAR domains may account for their opposing functions. The crystal structure of APPL BAR-PH heterodimer was solved to resolution2.8 A. Its overall structure exhibits crescent shape with a larger curvature radius of 76 A, compared to 55 A of the APPL1 BAR-PH homodimer. And the crystal structure APPL2 BAR-PH homodimer was solve to resolution 3.3 A. The overall structure of APPL2 BAR-PH homodimer is very similar to that of APPL BAR-PH heterodimer, but shows greater difference in curvature to the APPL1 BAR-PH homodimer structure. The concave side of APPL BAR-PH heterodimer and APPL2 BAR-PH homodimer all possess less positive charge than the APPL1 BAR-PH homodimer. Structural analysis reveals that leucine patches at the dimer interface may account for the formation of dimeric curve with certain curvature. Consequently, APPL2 BAR is able to enforce the curvature reduction to APPL1 BAR upon heterodimerization. In conclusion, the alterations of curvature and electrostasis are responsible for the modulation of endosome binding specificity and can elucidate the opposite roles of APPL1 and APPL2. LanCL2LanCL2 is a member of Lanthionine synthetase component C-like family. In human, LanCL2 binds to lanthionine derivatives and glutathione, participating in keeping intracellular reducing state. By binding to absiscic acid (ABA), LanCL2 is indispensible for the ABA-stimulated adipogenesis, insulin release, glucose homeostasis, and inflammatory response. It is also implicated in anticancer drug resistance. All these functions underscore the importance of LanCL2 in the diseases like diabetes, inflammation, and cancer.The crystal structure of LanCL2 was solved to resolution 1.8 A. The overall structure displays canonical double-layer α-barrel. The major differences from LanCL1 lay in the loops on the barrel top, which are implicated in various substrate bindings. A zinc-coordinating pocket was found among the loops, with conserved amino acid residues of distinct conformation. The electrostatic surface shows remarkable differences compared to that of LanCL1, suggesting that it may contribute to distinct substrate binding profile. Future implicationsAPPL proteins and LanCL proteins are all involved in the regulation of metabolism, such as glucose uptake, fatty acid oxidation, and insulin secretion, and play roles in diseases like obesity and type 2 diabete. Structural and functional studies of these proteins can provide insights into the molecular mechanisms and clues for related therapeutic approaches. DOI: 10.5353/th_b5043419 Subjects: Carrier proteinsCellular signal transduction

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