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Evolutionary selection of a 19-stranded mitochondrial ?-barrel scaffold bears structural and functional significance.

ABSTRACT: Transmembrane ?-barrels of eukaryotic outer mitochondrial membranes (OMMs) are major channels of communication between the cytosol and mitochondria and are indispensable for cellular homeostasis. A structurally intriguing exception to all known transmembrane ?-barrels is the unique odd-stranded, i.e. 19-stranded, structures found solely in the OMM. The molecular origins of this 19-stranded structure and its associated functional significance are unclear. In humans, the most abundant OMM transporter is the voltage-dependent anion channel. Here, using the human voltage-dependent anion channel as our template scaffold, we designed and engineered odd- and even-stranded structures of smaller (V216, V217, V218) and larger (V220, V221) barrel diameters. Determination of the structure, dynamics, and energetics of these engineered structures in bilayer membranes reveals that the 19-stranded barrel surprisingly holds modest to low stability in a lipid-dependent manner. However, we demonstrate that this structurally metastable protein possesses superior voltage-gated channel regulation, efficient mitochondrial targeting, and in vivo cell survival, with lipid-modulated stability, all of which supersede the occurrence of a metastable 19-stranded scaffold. We propose that the unique structural adaptation of these transmembrane transporters exclusively in mitochondria bears strong evolutionary basis and is functionally significant for homeostasis.

SUBMITTER: Srivastava SR

PROVIDER: S-EPMC7586230 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Evolutionary selection of a 19-stranded mitochondrial β-barrel scaffold bears structural and functional significance.

Srivastava Shashank Ranjan SR Mahalakshmi Radhakrishnan R

The Journal of biological chemistry 20200819 43

Transmembrane β-barrels of eukaryotic outer mitochondrial membranes (OMMs) are major channels of communication between the cytosol and mitochondria and are indispensable for cellular homeostasis. A structurally intriguing exception to all known transmembrane β-barrels is the unique odd-stranded, <i>i.e.</i> 19-stranded, structures found solely in the OMM. The molecular origins of this 19-stranded structure and its associated functional significance are unclear. In humans, the most abundant OMM t ...[more]

PMID: 32817169

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Project description:UnlabelledThe region consisting of the first and second variable regions (V1V2) of gp120 plays vital roles in the functioning of the HIV-1 envelope (Env). V1V2, which harbors multiple glycans and is highly sequence diverse, is located at the Env apex and stabilizes the trimeric gp120 spike on the virion surface. It shields V3 and the coreceptor binding sites in the prefusion state and exposes them upon CD4 binding. Data from the RV144 human HIV-1 vaccine trial suggested that antibody responses targeting the V1V2 region inversely correlated with the risk of infection; thus, understanding the antigenic structure of V1V2 can contribute to vaccine design. We have determined a crystal structure of a V1V2 scaffold molecule (V1V2ZM109-1FD6) in complex with 830A, a human monoclonal antibody that recognizes a V1V2 epitope overlapping the integrin-binding motif in V2. The structure revealed that V1V2 assumes a five-stranded beta barrel structure with the region of the integrin-binding site (amino acids [aa] 179 to 181) included in a "kink" followed by an extra beta strand. The complete barrel structure naturally presents the glycans on its outer surface and packs into its core conserved hydrophobic residues, including the Ile at position 181 which was highly correlated with vaccine efficacy in RV144. The epitope of monoclonal antibody 830A is discontinuous and composed of three segments: (i) Thr175, Tyr177, Leu179, and Asp180 at the kink overlapping the integrin-binding site; (ii) Arg153 and Val154 in V1; and (iii) Ile194 at the C terminus of V2. This report thus provides the atomic details of the immunogenic "V2i epitope."ImportanceData from the RV144 phase III clinical trial suggested that the presence of antibodies to the first and second variable regions (V1V2) of gp120 was associated with the modest protection afforded by the vaccine. V1V2 is a highly variable and immunogenic region of HIV-1 surface glycoprotein gp120, and structural information about this region and its antigenic landscape will be crucial in the design of an effective HIV-1 vaccine. We have determined a crystal structure of V1V2 in complex with human MAb 830A and have shown that MAb 830A recognizes a region overlapping the α4β7 integrin-binding site. We also showed that V1V2 forms a 5-stranded beta barrel, an elegant structure allowing sequence variations in the strand-connecting loops while preserving a conserved core.

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Evolutionary selection of a 19-stranded mitochondrial ?-barrel scaffold bears structural and functional significance.

Publications

Evolutionary selection of a 19-stranded mitochondrial β-barrel scaffold bears structural and functional significance.

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