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人类视锥-视杆同源盒转录因子的结构与功能分析。

Structural and functional analysis of the human cone-rod homeobox transcription factor.

机构信息

Department of Biology, James Madison University, Harrisonburg, Virginia, USA.

Department of Chemistry and Biochemistry, James Madison University, Harrisonburg, Virginia, USA.

出版信息

Proteins. 2022 Aug;90(8):1584-1593. doi: 10.1002/prot.26332. Epub 2022 Mar 23.

DOI:10.1002/prot.26332
PMID:35255174
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9271546/
Abstract

The cone-rod homeobox (CRX) protein is a critical K50 homeodomain transcription factor responsible for the differentiation and maintenance of photoreceptor neurons in the vertebrate retina. Mutant alleles in the human gene encoding CRX result in a variety of distinct blinding retinopathies, including retinitis pigmentosa, cone-rod dystrophy, and Leber congenital amaurosis. Despite the success of using in vitro biochemistry, animal models, and genomics approaches to study this clinically relevant transcription factor over the past 25 years since its initial characterization, there are no high-resolution structures in the published literature for the CRX protein. In this study, we use bioinformatic approaches and small-angle X-ray scattering (SAXS) structural analysis to further understand the biochemical complexity of the human CRX homeodomain (CRX-HD). We find that the CRX-HD is a compact, globular monomer in solution that can specifically bind functional cis-regulatory elements encoded upstream of retina-specific genes. This study presents the first structural analysis of CRX, paving the way for a new approach to studying the biochemistry of this protein and its disease-causing mutant protein variants.

摘要

锥体-杆同源盒（CRX）蛋白是一种关键的 K50 同源域转录因子，负责脊椎动物视网膜中光感受器神经元的分化和维持。编码 CRX 的人类基因中的突变等位基因导致多种不同的致盲性视网膜病变，包括色素性视网膜炎、锥杆营养不良和莱伯先天性黑蒙。尽管在过去的 25 年中，通过体外生物化学、动物模型和基因组学方法对该具有临床相关性的转录因子进行了研究，但在已发表的文献中，仍没有该 CRX 蛋白的高分辨率结构。在这项研究中，我们使用生物信息学方法和小角度 X 射线散射（SAXS）结构分析来进一步了解人类 CRX 同源域（CRX-HD）的生化复杂性。我们发现，CRX-HD 在溶液中是一个紧凑的球形单体，可特异性结合视网膜特异性基因上游编码的功能性顺式调控元件。本研究首次对 CRX 进行了结构分析，为研究该蛋白及其致病突变蛋白变体的生化特性开辟了新途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efc0/9543269/f77ea78eb03b/PROT-90-1584-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efc0/9543269/ffe73b8f2523/PROT-90-1584-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efc0/9543269/4d0355c6bfb7/PROT-90-1584-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efc0/9543269/409b77265781/PROT-90-1584-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efc0/9543269/24cdeb5934d0/PROT-90-1584-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efc0/9543269/f77ea78eb03b/PROT-90-1584-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efc0/9543269/ffe73b8f2523/PROT-90-1584-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efc0/9543269/4d0355c6bfb7/PROT-90-1584-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efc0/9543269/409b77265781/PROT-90-1584-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efc0/9543269/24cdeb5934d0/PROT-90-1584-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efc0/9543269/f77ea78eb03b/PROT-90-1584-g002.jpg

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