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    Understanding the architecture of mitochondrial presequence translocase machinery and its implications in ALS progression

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    Author
    Waingankar, Tejashree Pradip
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    Abstract
    The current thesis describes the structural organization of the presequence translocase machinery and its functional association with ALS pathogenesis. The TIM23 complex is essential for the mitochondrial biogenesis of polypeptides with N-terminus targeting sequence into the matrix and inner membrane. Hence any defects in the import machinery are known to cause mitochondrial dysfunction affecting cellular homeostasis. The importance of the presequence translocase machinery can be highlighted as its architecture, and overall import mechanisms have remained evolutionary conserved. However, because of the complex nature of a multicellular organism, the human TIM23 complex was proposed to have multiple forms distinguished by their role in housekeeping function and disease association. The findings of the current thesis provide insights into the structural dynamics of the human TIM23 machinery and how variants of an import motor complex protein differentially influence the matrix protein translocation. Additionally, the work focuses on the functional characterization of the presequence translocase machinery under a disease background, wherein the binding of mutant results in the altered translocation of a substrate leading to mitochondrial dysfunction.
    URI
    https://etd.iisc.ac.in/handle/2005/5950
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    • Biochemistry (BC) [259]

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