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Protein Kinase A Anchoring in Spermatozoan Function

蛋白激酶 A 锚定精子功能

基本信息

批准号：
8059915
负责人：
DANIEL W CARR
金额：
$ 3.21万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-01 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8059915
关键词：
A kinase anchoring protein Acrosome Reaction Binding Biochemical Calcium Catalytic Domain Chlamydomonas Cyclic AMP Cyclic AMP-Dependent Protein Kinases Defect Development Diagnosis Dimerization Docking Fertility Flagella Gene Targeting Germ Cells Goals Homologous Gene Homologous Protein Human Knockout Mice Knowledge Location Maintenance Male Contraceptive Agents Membrane Molecular Monitor Morphology Movement Mus Muscle Contraction Mutation Names Patients Peptides Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Protein Kinase Proteins Radial Reagent Research Personnel Rho-associated kinase Role Scaffolding Protein Signal Pathway Signal Transduction Signaling Molecule Smooth Muscle Sperm Motility Testing base cell motility design in vivo insight male novel programs protein kinase A kinase reproductive rho rhophilin scaffold sperm cell sperm function sperm protein yeast two hybrid system

项目摘要

DESCRIPTION: (provided by applicant) The cAMP-dependent protein kinase (PKA) is targeted to specific subcellular compartments through its interaction with A kinase anchoring proteins (AKAPs). Membrane permeable peptides, designed to disrupt PKA/AKAP interaction, inhibit sperm motility, suggesting PKA anchoring is required for the maintenance of motility. The overall goal of this proposal is to characterize the interaction of sperm AKAPs with the type two regulatory subunit of PKA (RII) and RII-homologues, and determine how these interactions regulate spermatozoan function(s). We will focus on two sperm AKAPs. AKAP110 is a predominant sperm AKAP and the focus of our previous proposal. Radial Spoke Protein 3 (RSP3) is a newly discovered AKAP in Chlamydomonas. It is the first flagellar AKAP to be found in the axoneme. Mutation of this protein disrupts flagellar beating. We have recently identified, cloned and expressed the human homolog of this protein. Based on the location of this AKAP, we hypothesize that RSP3 regulates motility by coordinating the action of kinases and/or phosphatases in the axoneme. We have recently identified four sperm-specific human proteins, in addition to PKA, which interact with sperm AKAP110. All of these proteins have a strong sequence similarity to the AKAP docking and dimerization domains of RII. Although these sperm proteins appear to be functional homologues of RII in their ability to bind AKAPs, they do not share other functions of RII such as the ability to bind cAMP or the catalytic subunit of PKA. Two of these RII homologues appear to be part of the Rho signaling pathway. One is homologous to murine ropporin. Ropporin is found along the principal piece of the flagellum and binds to rhophilin, a target protein for Rho. A second protein, named AKAP-associated sperm protein (ASP), is 39 percent identical with ropporin. Agents that inhibit Rho signaling inhibit sperm motility. One goal of this proposal is to test the hypothesis that Rho signaling regulates sperm motility via a mechanism similar to that observed in smooth muscle and that sperm AKAPs coordinate this mechanism by acting as scaffolding molecules. Studies outlined in this proposal should facilitate the design of new and highly specific pharmacological reagents for inhibiting sperm function in vivo. Knowledge gained from these studies may also be useful for the diagnosis and treatment of patients with defects in sperm movement and fertility.

描述：（由申请人提供）cAMP依赖性蛋白激酶（PKA）是通过与A的相互作用靶向特定的亚细胞区室激酶锚定蛋白（AKAP）。膜渗透性肽，设计用于破坏PKA/AKAP相互作用，抑制精子活力，提示PKA锚定是维持运动所必需的本提案的总体目标是是为了表征精子AKAP与2型调节因子的相互作用， PKA亚基（RII）和RII同源物，并确定这些相互作用调节精子功能。我们将重点介绍两种精子AKAP。AKAP 110是一个主要的精子AKAP和我们以前的建议的重点。径向辐条蛋白3（Protein 3，RSP 3）是在衣原体中新发现的一种AKAP。是第一鞭毛AKAP被发现在轴丝。这种蛋白质的突变破坏了鞭毛跳动我们最近鉴定、克隆并表达了人类这种蛋白质的同源物。根据AKAP的位置我们推测 RSP 3通过协调激酶的作用调节运动性和/或轴丝中的磷酸酶。我们最近发现了四种精子特异性人类蛋白质，除了PKA，与精子AKAP 110相互作用。所有这些蛋白质与AKAP对接具有很强的序列相似性， RII的二聚化结构域。尽管这些精子蛋白似乎 RII的功能同源物结合AKAP的能力，它们不共享 RII的其他功能，如结合cAMP或催化cAMP的能力， PKA亚基。其中两个RII同系物似乎是Rho的一部分，信号通路一个与鼠的ropporin同源。发现Ropporin 沿着鞭毛的主要部分，并结合到rhophilin，一个目标蛋白质Rho第二种蛋白质，称为AKAP相关精子蛋白（ASP），与Ropporin有39%的相同性。抑制Rho信号传导的药剂抑制精子活力。这个提议的一个目的是检验这个假设 Rho信号通过一种类似于在平滑肌中观察到，精子AKAP通过以下方式协调这种机制：作为支架分子。本建议中概述的研究应促进新型且高度特异性的药理学试剂的设计，在体内抑制精子功能。从这些研究中获得的知识也可能有助于诊断和治疗精子缺陷患者运动和生育。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Isolation and molecular characterization of AKAP110, a novel, sperm-specific protein kinase A-anchoring protein.

DOI：
10.1210/mend.13.5.0278
发表时间：
1999-05
期刊：
Molecular endocrinology
影响因子：
0
作者：
Srinivasan Vijayaraghavan;Greg A. Liberty;Jag Mohan;V. Winfrey;G. E. Olson;Daniel W. Carr
通讯作者：
Srinivasan Vijayaraghavan;Greg A. Liberty;Jag Mohan;V. Winfrey;G. E. Olson;Daniel W. Carr

Expression and intracellular localization of protein phosphatases 2A and 2B, protein kinase a, A-Kinase anchoring protein (AKAP79), and binding of the regulatory (RII) subunit of protein kinase a to AKAP79 in human myometrium.

人子宫肌层中蛋白磷酸酶 2A 和 2B、蛋白激酶 a、A-激酶锚定蛋白 (AKAP79) 的表达和细胞内定位，以及蛋白激酶 a 的调节 (RII) 亚基与 AKAP79 的结合。