Primary response of the sGC heme binding domain to the cleavage of the Fe-His bond.

Huali Zhang,Zhengqiang Li,Yuebin Zhang,Ming Lu

doi:10.6026/97320630002296

Abstract

Soluble guanylate cyclase (sGC) is an important heme sensor protein. Regulation of the status of heme in the heme binding domain (or HNOX domain) by various gaseous activators can increase the catalytic efficiency of the cyclase domain. Several studies have demonstrated that the full activation of sGC is directly related to the cleavage of the Fe-His bond of the HNOX domain. To expand the primary response of the sGC HNOX domain to the cleavage event, a structural model of the sGC HNOX domain was constructed using homology modeling and the Fe-His bond was released at 6 ns of a 10-ns molecular dynamics simulation. An instant increment of Calpha-RMSD over L2 (Loop2, residues 124-130) was found after the cleavage of the Fe-His bond, which was consistent with the principle component analysis (PCA). The energy analysis results suggest that the motions of L2 are energetic. Based on the results, energetic conformational transformation of L2 is identified as the primary response of the sGC HNOX domain to the cleavage of the Fe-His bond.

Highlights

The functional heme sensor proteins contain both the heme binding domain and the catalytic domain.The transmission of the binding signals of the heme moiety induced by various gaseous activators from the heme binding domain to the catalytic domain is essential for regulation of protein activity
The objective of this study was to explore the primary response of the Soluble guanylate cyclase (sGC) HNOX domain to the cleavage of the Fe-His bond
The energetic conformational transformation of L2 is identified as the primary response of the HNOX domain to the cleavage of the Fe-His bond

Summary

Introduction

The functional heme sensor proteins contain both the heme binding domain and the catalytic domain. The transmission of the binding signals of the heme moiety induced by various gaseous activators from the heme binding domain to the catalytic domain is essential for regulation of protein activity. Soluble guanylate cyclase (sGC), a significant heme sensor protein, catalyzes the conversion of GTP to cGMP in vivo. Mammalian sGC is a heterodimeric heme enzyme composed of one α subunit and one β subunit. The heme prosthetic group is bound to the sGC heme binding domain (or heme nitric oxide and/or oxygen binding domain, HNOX domain) of the β subunit via the coordinated bond with β105-His and is stabilized through the interaction of its propionic acid groups with

Objectives

Findings

Discussion

Conclusion