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一个熔融球蛋白集合使 Arf1-GDP 为核苷酸开关做好准备。

A molten globule ensemble primes Arf1-GDP for the nucleotide switch.

机构信息

Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180.

Graduate Program in Biochemistry and Biophysics, School of Science, Rensselaer Polytechnic Institute, Troy, NY 12180.

出版信息

Proc Natl Acad Sci U S A. 2024 Sep 24;121(39):e2413100121. doi: 10.1073/pnas.2413100121. Epub 2024 Sep 18.

DOI:10.1073/pnas.2413100121
PMID:39292747
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11441498/
Abstract

The adenosine di-phosphate (ADP) ribosylation factor (Arf) small guanosine tri-phosphate (GTP)ases function as molecular switches to activate signaling cascades that control membrane organization in eukaryotic cells. In Arf1, the GDP/GTP switch does not occur spontaneously but requires guanine nucleotide exchange factors (GEFs) and membranes. Exchange involves massive conformational changes, including disruption of the core β-sheet. The mechanisms by which this energetically costly switch occurs remain to be elucidated. To probe the switch mechanism, we coupled pressure perturbation with nuclear magnetic resonance (NMR), Fourier Transform infra-red spectroscopy (FTIR), small-angle X-ray scattering (SAXS), fluorescence, and computation. Pressure induced the formation of a classical molten globule (MG) ensemble. Pressure also favored the GDP to GTP transition, providing strong support for the notion that the MG ensemble plays a functional role in the nucleotide switch. We propose that the MG ensemble allows for switching without the requirement for complete unfolding and may be recognized by GEFs. An MG-based switching mechanism could constitute a pervasive feature in Arfs and Arf-like GTPases, and more generally, the evolutionarily related (Ras-like small GTPases) Rags and Gα GTPases.

摘要

腺苷二磷酸（ADP）核糖基化因子（Arf）小分子鸟苷三磷酸（GTP）酶作为分子开关，激活信号级联反应，控制真核细胞的膜组织。在 Arf1 中，GDP/GTP 开关不是自发发生的，而是需要鸟嘌呤核苷酸交换因子（GEF）和膜。交换涉及大规模的构象变化，包括核心β-片层的破坏。这种能量昂贵的开关发生的机制仍有待阐明。为了研究开关机制，我们将压力扰动与核磁共振（NMR）、傅里叶变换红外光谱（FTIR）、小角 X 射线散射（SAXS）、荧光和计算相结合。压力诱导形成经典的无规卷曲（MG） ensemble。压力也有利于 GDP 向 GTP 的转变，为 MG ensemble 在核苷酸开关中发挥功能作用的观点提供了强有力的支持。我们提出，MG ensemble 允许在不需要完全展开的情况下进行切换，并且可能被 GEF 识别。基于 MG 的切换机制可能构成 Arfs 和 Arf 样 GTP 酶，以及更普遍的进化相关的（Ras 样小 GTP 酶）Rags 和 Gα GTP 酶的普遍特征。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/e2a57b0b1639/pnas.2413100121fig08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/e61da961f761/pnas.2413100121fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/d9ecbf94a3af/pnas.2413100121fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/f628b50ccbf4/pnas.2413100121fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/8424c9b5a5c2/pnas.2413100121fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/77f12f8e996f/pnas.2413100121fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/371274032fec/pnas.2413100121fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/eef0ec0b4802/pnas.2413100121fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/e2a57b0b1639/pnas.2413100121fig08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/e61da961f761/pnas.2413100121fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/d9ecbf94a3af/pnas.2413100121fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/f628b50ccbf4/pnas.2413100121fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/8424c9b5a5c2/pnas.2413100121fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/77f12f8e996f/pnas.2413100121fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/371274032fec/pnas.2413100121fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/eef0ec0b4802/pnas.2413100121fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03de/11441498/e2a57b0b1639/pnas.2413100121fig08.jpg

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