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Dissecting Substrate Specificities of the Mitochondrial AFG3L2 Protease

机译：解剖线粒体AFG3L2蛋白酶的底物特异性

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摘要

Human AFG3L2 is a compartmental AAA+ protease that performs ATP-fueled degradation at the matrix face of the inner mitochondrial membrane. Identifying how AFG3L2 selects substrates from the diverse complement of matrix- localized proteins is essential for understanding mitochondria' protein biogenesis and quality control. Here, we create solubilized forms of AFG3L2 to examine the enzyme's substrate specificity mechanisms. We show that conserved residues within the presequence of the mitochondrial ribosomal protein, MrpL32, target the subunit to the protease for processing into a mature form. Moreover, these residues can act as a degron, delivering diverse model proteins to AFG3L2 for degradation. By determining the sequence of degradation products from multiple substrates using mass spectrometry, we construct a peptidase specificity profile that displays constrained product lengths and is dominated by the identity of the residue at the P1' position, with a strong preference for hydrophobic and small polar residues. This specificity profile is validated by examining the cleavage of both fluorogenic reporter peptides and full polypeptide substrates bearing different P1' residues. Together, these results demonstrate that AFG3L2 contains multiple modes of specificity, discriminating between potential substrates by recognizing accessible degron sequences and performing peptide bond cleavage at preferred patterns of residues within the compartmental chamber.
机译：人AFG3L2是分区AAA +蛋白酶，其在内部线粒体膜的基质面上进行ATP燃料降解。鉴定AFG3L2如何从基质局部化蛋白质的各种补充中选择底物对于了解线粒体蛋白生物发生和质量控制至关重要。在这里，我们创建溶解形式的AFG3L2，以检查酶的底物特异性机制。我们表明，在线粒体核糖体蛋白MRPL32的PRESEQUENCE内的保守残留物靶向蛋白酶的亚基以加工成成熟的形式。此外，这些残留物可以用作血管，将不同的模型蛋白质递送至AFG3L2以进行降解。通过使用质谱法测定来自多个底物的降解产物的序列，我们构建肽酶特异性曲线，其显示受约束的产品长度，并以P1'位置的残基的同一性为主，具有疏水性和小极性残留物的强烈偏好。通过检查含有不同P1'残基的荧光报道肽和全多肽基材的裂解来验证该特异性分布。这些结果表明，AFG3L2含有多种特异性模式，通过识别可访问的血管序列和在隔室室内的残留物的优选模式下进行肽键裂解来区分电母基质。

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  • 来源
    《Biochemistry》 |2018年第28期|共11页
  • 作者

    Ding Bojian; Martin Dwight W.; Rampello Anthony J.; Glynn Steven E.;

  • 作者单位

    SUNY Stony Brook Dept Biochem &

    Cell Biol Stony Brook NY 11794 USA;

    SUNY Stony Brook Dept Med Stony Brook NY 11794 USA;

    SUNY Stony Brook Dept Biochem &

    Cell Biol Stony Brook NY 11794 USA;

    SUNY Stony Brook Dept Biochem &

    Cell Biol Stony Brook NY 11794 USA;

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  • 正文语种 eng
  • 中图分类 生物化学;
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