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PDIP38 is a novel adaptor-like modulator of the mitochondrial AAA+ protease CLPXP
bioRxiv - Biochemistry Pub Date : 2020-05-22 , DOI: 10.1101/2020.05.19.105320
Philip R. Strack , Erica J. Brodie , Hanmiao Zhan , Verena J. Schuenemann , Liz J. Valente , Tamanna Saiyed , Kornelius Zeth , Kaye N. Truscott , David A. Dougan

Polymerase δ interacting protein of 38 kDa (PDIP38) was originally identified in a yeast two hybrid screen as an interacting protein of DNA polymerase delta, more than a decade ago. Since this time several subcellular locations have been reported and hence its function remains controversial. Our current understanding of PDIP38 function has also been hampered by a lack of detailed biochemical or structural analysis of this protein. Here we show, that human PDIP38 is directed to the mitochondrion, where it resides in the matrix compartment, together with its partner protein CLPX. PDIP38 is a bifunctional protein, composed of two conserved domains separated by an α-helical hinge region (or middle domain). The N-terminal (YccV-like) domain of PDIP38 forms an SH3-like β-barrel, which interacts specifically with CLPX, via the adaptor docking loop within the N-terminal Zinc binding domain (ZBD) of CLPX. In contrast, the C-terminal (DUF525) domain forms an Immunoglobin-like β-sandwich fold, which contains a highly conserved hydrophobic groove. Based on the physicochemical properties of this groove, we propose that PDIP38 is required for the recognition (and delivery to CLPXP) of proteins bearing specific hydrophobic degrons, potentially located at the termini of the target protein. Significantly, interaction with PDIP38 stabilizes the steady state levels of CLPX in vivo. Consistent with these data, PDIP38 inhibits the LONM-mediated turnover of CLPX in vitro. Collectively, our findings shed new light on the mechanistic and functional significance of PDIP38, indicating that in contrast to its initial identification as a nuclear protein, PIDP38 is a bona fide mitochondrial adaptor protein for the CLPXP protease.

中文翻译:

PDIP38是线粒体AAA +蛋白酶CLPXP的新型适配器样调节剂

十多年前,38kDa的聚合酶δ相互作用蛋白(PDIP38)最初在酵母2杂种筛选中被鉴定为DNA聚合酶δ的相互作用蛋白。自从这段时间以来,已经报道了几个亚细胞的位置,因此其功能仍然存在争议。由于缺乏对该蛋白的详细生化或结构分析,我们目前对PDIP38功能的理解也受到阻碍。在这里,我们显示人PDIP​​38及其伴侣蛋白CLPX被定向到线粒体,该线粒体位于基质区室。PDIP38是一种双功能蛋白,由被α-螺旋铰链区(或中间结构域)隔开的两个保守结构域组成。PDIP38的N末端(YccV样)域形成SH3样β桶,与CLPX特异性相互作用,通过CLPX的N端锌结合结构域(ZBD)内的衔接子对接环。相反,C末端(DUF525)域形成免疫球蛋白样的β夹心折叠,其中包含高度保守的疏水沟。基于此凹槽的物理化学性质,我们建议PDIP38是识别(可能传递至目标蛋白末端的)带有特定疏水性退化子的蛋白(并将其传递至CLPXP所必需的)。重要的是,与PDIP38的相互作用可稳定体内CLPX的稳态水平。与这些数据一致,PDIP38在体外抑制LONM介导的CLPX转换。总的来说,我们的发现为PDIP38的机理和功能意义提供了新的线索,表明与最初鉴定为核蛋白的相反,
更新日期:2020-05-22
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