The C-Terminal of NaV1.7 Is Ubiquitinated by NEDD4L

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Bio & Med Chem Au Pub Date : 2023-10-13 DOI:10.1021/acsbiomedchemau.3c00031

Katharine M. Wright, Hanjie Jiang, Wendy Xia, Michael B. Murphy, Tatiana N. Boronina, Justin N. Nwafor, HyoJeon Kim, Akunna M. Iheanacho, P. Aitana Azurmendi, Robert N. Cole, Philip A. Cole and Sandra B. Gabelli*,

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Abstract

Na_V1.7, the neuronal voltage-gated sodium channel isoform, plays an important role in the human body’s ability to feel pain. Mutations within Na_V1.7 have been linked to pain-related syndromes, such as insensitivity to pain. To date, the regulation and internalization mechanisms of the Na_V1.7 channel are not well known at a biochemical level. In this study, we perform biochemical and biophysical analyses that establish that the HECT-type E3 ligase, NEDD4L, ubiquitinates the cytoplasmic C-terminal (CT) region of Na_V1.7. Through in vitro ubiquitination and mass spectrometry experiments, we identify, for the first time, the lysine residues of Na_V1.7 within the CT region that get ubiquitinated. Furthermore, binding studies with an NEDD4L E3 ligase modulator (ubiquitin variant) highlight the dynamic partnership between NEDD4L and Na_V1.7. These investigations provide a framework for understanding how NEDD4L-dependent regulation of the channel can influence the Na_V1.7 function.

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NaV1.7 的 C 端被 NEDD4L 泛素化

神经元电压门控钠通道同工型 NaV1.7 在人体感受疼痛的能力中发挥着重要作用。NaV1.7 的突变与疼痛相关综合症（如对疼痛不敏感）有关。迄今为止，NaV1.7 通道的调控和内化机制在生化水平上还不是很清楚。在这项研究中，我们进行了生化和生物物理分析，确定了 HECT 型 E3 连接酶 NEDD4L 泛素化 NaV1.7 的细胞质 C 端（CT）区域。通过体外泛素化和质谱分析实验，我们首次确定了NaV1.7在CT区域内被泛素化的赖氨酸残基。此外，与 NEDD4L E3 连接酶调节剂（泛素变体）的结合研究突出了 NEDD4L 和 NaV1.7 之间的动态伙伴关系。这些研究为了解 NEDD4L 依赖性调控通道如何影响 NaV1.7 功能提供了一个框架。

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ACS Bio & Med Chem Au 药物、生物、化学-

CiteScore

4.10

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0.00%

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期刊介绍： ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.

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