CRIS—A Novel cAMP-Binding Protein Controlling Spermiogenesis and the Development of Flagellar Bending

Anke Miriam Krähling,Eberhard Krause,Luis Alvarez,Dagmar Wachten,Timo Strünker,Monika Gunkel,Ashraf Al-Amoudi,Simone Wörtge,Katharina Debowski,Ulrich Benjamin Kaupp,Ingo Weyand,Reinhard Seifert,Ari Waisman,Stephan Irsen,Qui Van,Elisabeth Kremmer,Ingo Voigt

doi:10.1371/journal.pgen.1003960

Abstract

The second messengers cAMP and cGMP activate their target proteins by binding to a conserved cyclic nucleotide-binding domain (CNBD). Here, we identify and characterize an entirely novel CNBD-containing protein called CRIS (cyclic nucleotide receptor involved in sperm function) that is unrelated to any of the other members of this protein family. CRIS is exclusively expressed in sperm precursor cells. Cris-deficient male mice are either infertile due to a lack of sperm resulting from spermatogenic arrest, or subfertile due to impaired sperm motility. The motility defect is caused by altered Ca2+ regulation of flagellar beat asymmetry, leading to a beating pattern that is reminiscent of sperm hyperactivation. Our results suggest that CRIS interacts during spermiogenesis with Ca2+-regulated proteins that—in mature sperm—are involved in flagellar bending.

Highlights

Cyclic nucleotide-binding proteins play a prominent role in cellular signaling
Their activity is regulated by binding of cAMP and/or cGMP to a highly conserved cyclic nucleotide-binding domain (CNBD), consisting of eight beta sheets that are flanked by three alpha helices [1]
We report on the identification and functional characterization of an entirely novel member of the CNBD-containing protein family, which we call CRIS

Summary

Introduction

Cyclic nucleotide-binding proteins play a prominent role in cellular signaling. Their activity is regulated by binding of cAMP and/or cGMP to a highly conserved cyclic nucleotide-binding domain (CNBD), consisting of eight beta sheets that are flanked by three alpha helices [1]. The binding of ligand is conveyed to different effector domains like a catalytic kinase domain or a channel gate [9], the CNBD is highly conserved in all those proteins. We report on the identification and functional characterization of an entirely novel member of the CNBD-containing protein family, which we call CRIS (cyclic nucleotide receptor involved in sperm function). We show that CRIS controls sperm function and, thereby, male fertility

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