Structural and functional divergence of GDAP1 from the glutathione S-transferase superfamily.
Structural and functional divergence of GDAP1 from the glutathione S-transferase superfamily.
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DOI：
10.1096/fj.202000110r
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发表时间：
2020-05
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影响因子：
--
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中科院分区：
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神经节苷脂诱导的分化相关蛋白1 （GDAP1）突变改变线粒体形态并导致遗传性周围神经病变charco - marie - tooth病的几种亚型；然而，GDAP1的作用机制仍然是难以捉摸的。GDAP1含有与GST超家族同源的一级序列；然而，GDAP1是否是一项有效的商品及服务税的问题尚未得到明确解决。在这里，我们提出了生化证据，表明GDAP1已经失去了结合谷胱甘肽的能力，但没有失去底物结合活性。我们发现位于h位点基序内的α-环是底物结合的主要决定因素。利用GDAP1的结构数据，我们发现GDAP1中通常与谷胱甘肽相互作用的g位点的关键残基和构型被改变，使其无法结合谷胱甘肽。最后，我们发现GDAP1在HeLa细胞中的过表达导致线粒体表型不同于氧化应激诱导的线粒体断裂。这种表型依赖于跨膜结构域的存在，以及在典型gst中未发现的独特疏水结构域。总之，我们的数据指向GDAP1的非酶作用，如传感器或受体。
Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) alter mitochondrial morphology and result in several subtypes of the inherited peripheral neuropathy Charcot-Marie-Tooth disease; however, the mechanism by which GDAP1 functions has remained elusive. GDAP1 contains primary sequence homology to the GST superfamily; however, the question of whether GDAP1 is an active GST has not been clearly resolved. Here, we present biochemical evidence, suggesting that GDAP1 has lost the ability to bind glutathione without a loss of substrate binding activity. We have revealed that the α-loop, located within the H-site motif is the primary determinant for substrate binding. Using structural data of GDAP1, we have found that critical residues and configurations in the G-site which canonically interact with glutathione are altered in GDAP1, rendering it incapable of binding glutathione. Last, we have found that the overexpression of GDAP1 in HeLa cells results in a mitochondrial phenotype which is distinct from oxidative stress-induced mitochondrial fragmentation. This phenotype is dependent on the presence of the transmembrane domain, as well as a unique hydrophobic domain that is not found in canonical GSTs. Together, we data point toward a non-enzymatic role for GDAP1, such as a sensor or receptor.
影响因子：
3.1
作者：
Juárez P;Palau F
通讯作者：
Palau F