Matsushima Norio, Takatsuka Shintaro, Miyashita Hiroki, Kretsinger Robert H
Center for Medical Education, Sapporo Medical University, Sapporo 060-8556, Japan.
Institute of Tandem Repeats, Noboribetsu 059-0464, Japan.
Protein Pept Lett. 2019;26(2):108-131. doi: 10.2174/0929866526666181208170027.
Mutations in the genes encoding Leucine Rich Repeat (LRR) containing proteins are associated with over sixty human diseases; these include high myopia, mitochondrial encephalomyopathy, and Crohn's disease. These mutations occur frequently within the LRR domains and within the regions that shield the hydrophobic core of the LRR domain. The amino acid sequences of fifty-five LRR proteins have been published. They include Nod-Like Receptors (NLRs) such as NLRP1, NLRP3, NLRP14, and Nod-2, Small Leucine Rich Repeat Proteoglycans (SLRPs) such as keratocan, lumican, fibromodulin, PRELP, biglycan, and nyctalopin, and F-box/LRR-repeat proteins such as FBXL2, FBXL4, and FBXL12. For example, 363 missense mutations have been identified. Replacement of arginine, proline, or cysteine by another amino acid, or the reverse, is frequently observed. The diverse effects of the mutations are discussed based on the known structures of LRR proteins. These mutations influence protein folding, aggregation, oligomerization, stability, protein-ligand interactions, disulfide bond formation, and glycosylation. Most of the mutations cause loss of function and a few, gain of function.
编码富含亮氨酸重复序列（LRR）蛋白的基因突变与六十多种人类疾病相关；这些疾病包括高度近视、线粒体脑肌病和克罗恩病。这些突变频繁发生在LRR结构域内以及屏蔽LRR结构域疏水核心的区域内。五十五种LRR蛋白的氨基酸序列已公布。它们包括Nod样受体（NLR），如NLRP1、NLRP3、NLRP14和Nod-2；小富含亮氨酸重复序列蛋白聚糖（SLRP），如角膜蛋白聚糖、光蛋白聚糖、纤调蛋白、脯氨酸丰富的细胞外基质蛋白、双糖链蛋白聚糖和夜盲蛋白；以及F-box/LRR重复蛋白，如FBXL2、FBXL4和FBXL12。例如，已鉴定出363个错义突变。经常观察到精氨酸、脯氨酸或半胱氨酸被另一种氨基酸取代，或反之。基于LRR蛋白的已知结构讨论了这些突变的多种影响。这些突变影响蛋白质折叠、聚集、寡聚化、稳定性、蛋白质-配体相互作用、二硫键形成和糖基化。大多数突变导致功能丧失，少数导致功能获得。
