Wieland Thomas, Attwood Paul V
Institute for Experimental and Clinical Pharmacology and Toxicology, Mannheim Medical Faculty, Heidelberg University , Mannheim, Germany.
School of Chemistry and Biochemistry, The University of Western Australia , Crawley, Australia.
Front Pharmacol. 2015 Aug 21;6:173. doi: 10.3389/fphar.2015.00173. eCollection 2015.
Reversible phosphorylation of amino acid side chains in proteins is a frequently used mechanism in cellular signal transduction and alterations of such phosphorylation patterns are very common in cardiovascular diseases. They reflect changes in the activities of the protein kinases and phosphatases involving signaling pathways. Phosphorylation of serine, threonine, and tyrosine residues has been extensively investigated in vertebrates, whereas reversible histidine phosphorylation, a well-known regulatory signal in lower organisms, has been largely neglected as it has been generally assumed that histidine phosphorylation is of minor importance in vertebrates. More recently, it has become evident that the nucleoside diphosphate kinase isoform B (NDPK-B), an ubiquitously expressed enzyme involved in nucleotide metabolism, and a highly specific phosphohistidine phosphatase (PHP) form a regulatory histidine protein kinase/phosphatase system in mammals. At least three well defined substrates of NDPK-B are known: The β-subunit of heterotrimeric G-proteins (Gβ), the intermediate conductance potassium channel SK4 and the Ca(2+) conducting TRP channel family member, TRPV5. In each of these proteins the phosphorylation of a specific histidine residue regulates cellular signal transduction or channel activity. This article will therefore summarize our current knowledge on protein histidine phosphorylation and highlight its relevance for cardiovascular physiology and pathophysiology.
蛋白质中氨基酸侧链的可逆磷酸化是细胞信号转导中常用的机制，这种磷酸化模式的改变在心血管疾病中非常常见。它们反映了涉及信号通路的蛋白激酶和磷酸酶活性的变化。丝氨酸、苏氨酸和酪氨酸残基的磷酸化在脊椎动物中已得到广泛研究，而可逆的组氨酸磷酸化，作为低等生物中一种著名的调节信号，在很大程度上被忽视了，因为人们普遍认为组氨酸磷酸化在脊椎动物中不太重要。最近，很明显核苷二磷酸激酶同工型B（NDPK-B），一种参与核苷酸代谢的普遍表达的酶，和一种高度特异性的磷酸组氨酸磷酸酶（PHP）在哺乳动物中形成了一个调节性组氨酸蛋白激酶/磷酸酶系统。已知NDPK-B至少有三种明确的底物：异源三聚体G蛋白（Gβ）的β亚基、中等电导钾通道SK4和Ca(2+)传导TRP通道家族成员TRPV5。在这些蛋白质中的每一种中，特定组氨酸残基的磷酸化调节细胞信号转导或通道活性。因此，本文将总结我们目前关于蛋白质组氨酸磷酸化的知识，并强调其对心血管生理和病理生理的相关性。
