STAND, a Class of P-Loop NTPases Including Animal and Plant Regulators of Programmed Cell Death: Multiple, Complex Domain Architectures, Unusual Phyletic Patterns, and Evolution by Horizontal Gene Transfer

Abstract

Using sequence profile analysis and sequence-based structure predictions, we define a previously unrecognized, widespread class of P-loop NTPases. The signal transduction ATPases with numerous domains (STAND) class includes the AP-ATPases (animal apoptosis regulators CED4/Apaf-1, plant disease resistance proteins, and bacterial AfsR-like transcription regulators) and NACHT NTPases (e.g. NAIP, TLP1, Het-E-1) that have been studied extensively in the context of apoptosis, pathogen response in animals and plants, and transcriptional regulation in bacteria. We show that, in addition to these well-characterized protein families, the STAND class includes several other groups of (predicted) NTPase domains from diverse signaling and transcription regulatory proteins from bacteria and eukaryotes, and three Archaea-specific families. We identified the STAND domain in several biologically well-characterized proteins that have not been suspected to have NTPase activity, including soluble adenylyl cyclases, nephrocystin 3 (implicated in polycystic kidney disease), and Rolling pebble (a regulator of muscle development); these findings are expected to facilitate elucidation of the functions of these proteins. The STAND class belongs to the additional strand, catalytic E division of P-loop NTPases together with the AAA+ ATPases, RecA/helicase-related ATPases, ABC-ATPases, and VirD4/PilT-like ATPases. The STAND proteins are distinguished from other P-loop NTPases by the presence of unique sequence motifs associated with the N-terminal helix and the core strand-4, as well as a C-terminal helical bundle that is fused to the NTPase domain. This helical module contains a signature GxP motif in the loop between the two distal helices. With the exception of the archaeal families, almost all STAND NTPases are multidomain proteins containing three or more domains. In addition to the NTPase domain, these proteins typically contain DNA-binding or protein-binding domains, superstructure-forming repeats, such as WD40 and TPR, and enzymatic domains involved in signal transduction, including adenylate cyclases and kinases. By analogy to the AAA+ ATPases, it can be predicted that STAND NTPases use the C-terminal helical bundle as a "lever" to transmit the conformational changes brought about by NTP hydrolysis to effector domains. STAND NTPases represent a novel paradigm in signal transduction, whereby adaptor, regulatory switch, scaffolding, and, in some cases, signal-generating moieties are combined into a single polypeptide. The STAND class consists of 14 distinct families, and the evolutionary history of most of these families is riddled with dramatic instances of lineage-specific expansion and apparent horizontal gene transfer. The STAND NTPases are most abundant in developmentally and organizationally complex prokaryotes and eukaryotes. Transfer of genes for STAND NTPases from bacteria to eukaryotes on several occasions might have played a significant role in the evolution of eukaryotic signaling systems.

Guanylyl Cyclase Protein and cGMP Product Independently Control Front and Back of ChemotaxingDictyosteliumCells

“…The sequence of the C-terminal domain of sGC has been well conserved throughout evolution with orthologues in bacterial kinases and soluble adenylyl cyclases. The domain contains a highly conserved P-loop ATPase motif that classifies sGC as a member of the AAAϩ protein family (Leipe et al, 2004). Members of this family have been shown to use the energy released by the ATPase activity to generate mechanical force (Neuwald et al, 1999).…”

A new CARD15 mutation in Blau syndrome

“…This search returned many members of the NACHT domain subfamily. 26,27 E383 is conserved in 85 of the 138 sequences (61.6%) included in the complete NACHT domain sequence alignment of the Pfam database (release 15.0), 28 which indicates a higher evolutionary conservation than that of other residues mutated in BS: R334, conserved in 67 sequences (48.6%), and L469, contained in an unconserved loop after the C-terminus of the Pfam NACHT alignment. For the sake of simplicity, we selected the closely related CARD15, CARD4 and PYPAF1-8 proteins containing the CARD and PYD domain, respectively, for further analyses (Figure 2).…”

“…27 In most proteins, the NACHT domain is centrally located between a C-terminal sensor domain (LRRs in CARD15/4 and PYPAF1-8) and an N-terminal adaptor domain (CARD/ PYD). According to current models, the NACHT domain undergoes, in response to a specific ligand -LRR interaction, stereotyped, NTPase-mediated conformational changes that involve homophilic oligomerization, recruitment of downstream factors, and assembly and dissolution of a signaling complex eventually leading to NF-kB activation.…”

“…11 -14,27,34 A similar switch changing between an inactive ADP-bound and an active ATP-hydrolyzing conformation functions in the NACHT-related NBDs of apoptotic protease-activating factor 1 (APAF1), with a WD40 repeat sensor domain and a CARD adaptor domain regulating apoptosome activation, 35 and of plant disease resistance proteins, activated by pathogen recognition through their LRRs. 15,16 This regulatory NTPase switch can be compared with that described in detail for other ATPases such as the valosin-containing protein p97, 36,37 a member of the NACHT/STAND-related AAA þ family, 27 and trimeric G proteins. 37 -39 In all cases, NTPase domains are generally assumed to work in signaling cascades and to provide scaffolds for NTP-dependent assembly of protein complexes that integrate signals transmitted by different sensor domains.…”

SanG, a transcriptional activator, controls nikkomycin biosynthesis through binding to the sanN–sanO intergenic region in Streptomyces ansochromogenes

“…The N-terminal 300 aa residues of SanG containing the OmpR-like DNA-binding domain showed significant sequence similarity with several pathway-specific regulators of the SARP family that appear to turn on the expression of at least some of the genes of their respective clusters, and in turn to control antibiotic production. The central region of SanG displays an ATP/ GTP-binding AAA domain that has characteristics of a large family of ATPases associated with diverse cellular activities, including cell-cycle regulation, protein degradation and protein transport (Leipe et al, 2004). Deletion of sanG had pleiotropic effects on secondary metabolism and development, but the C-terminal region was not essential for the development of S. ansochromogenes (Liu et al, 2005).…”