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Abstract
Prototype member of the membrane guanylate cyclase family, ANF-RGC (Atrial Natriuretic Factor Receptor Guanylate Cyclase), is the physiological signal transducer of two most hypotensive hormones ANF and BNP, and of the intracellular free Ca2+. Both the hormonal and the Ca2+-modulated signals operate through a common second messenger, cyclic GMP; yet, their operational modes are divergent. The hormonal pathways originate at the extracellular domain of the guanylate cyclase; and through a cascade of structural changes in its successive domains activate the C-terminal catalytic domain (CCD). In contrast, the Ca2+ signal operating via its sensor, myristoylated neurocalcin δ both originates and is translated directly at the CCD. Through a detailed sequential deletion and expression analyses, the present study examines the role of the signaling helix domain (SHD) in these two transduction pathways. SHD is a conserved 35-amino acid helical region of the guanylate cyclase, composed of five heptads, each meant to tune and transmit the hormonal signals to the CCD for their translation and generation of cyclic GMP. Its structure is homo-dimeric and the molecular docking analyses point out to the possibility of antiparallel arrangement of the helices. Contrary to the hormonal signaling, SHD has no role in regulation of the Ca2+- modulated pathway. The findings establish and define in molecular terms the presence of two distinct non-overlapping transduction modes of ANF-RGC, and for the first time demonstrate how differently they operate, and, yet generate cyclic GMP utilizing common CCD machinery.
Highlights
Kick started by historic discovery of the prototype ANF-RGC (Atrial Natriuretic Factor Receptor Guanylate Cyclase) (Paul, 1986; Paul et al, 1987), the membrane guanylate cyclase (MGC) field has expanded to constitute a family of seven - -ANF-RGC, CNP-RGC, stable enterotoxin (STa)-RGC, ROS-GC1, ROS-GC2, ONE-GC and GC-G [reviewed in terminology: (Sharma et al, 2016)]
Since ANF-RGC, like other membrane guanylate cyclases, exists as a homodimer with its catalytic domain in antiparallel, wreath-like orientation (Ravichandran et al, 2017), the question was: what is the configurational positioning of the monomers within the signaling helix domain (SHD) dimer? Two molecular docking programs (M-ZDOCK2 and Z-DOCK3) were used for the analyses
This study represents a continuation of the saga on the development of the membrane guanylate cyclase (MGC) field and is a part of the overall goal of decoding the molecular principles governing the transduction machineries of various MGCs
Summary
By synthesizing cellular second messenger cyclic GMP the family is interlocked with the diverse physiological processes ranging from cardiac vasculature to cellular growth, sensory transductions, neural plasticity, temperature sensing and pineallinked brain functions (reviewed and Figure 10 in Sharma et al, 2016) These processes are compromised by natural mutations incurred in their key genes (discussed in Duda et al, 2018); a few examples are: CNP-RGC-R819C causes acromesomelic dysplasia (Vasques et al, 2013; Nakao et al, 2015); and more than 100 ROS-GC1 mutations result in retinal dystrophies, mainly Leber’s congenital amaurosis (LCA1) and cone-rod degeneration (CORD6) (Perrault et al, 1996, 1999; Kelsell et al, 1998; Wilkie et al, 2000; Rozet et al, 2001; Hunt et al, 2010; Gradstein et al, 2016). The gene encoding ONEGC is rodent-specific, not present in the humans (Torrents et al, 2003; Caenepeel et al, 2004; Young et al, 2007)
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