Low-resolution structural studies of human Stanniocalcin-1

Background: The molecular mechanisms behind previously reported biological effects of stanniocalcin-1 are poorly understood. Results: Stanniocalcin-1 potently inhibits the proteolytic activity of the metzincin metalloproteinases PAPP-A and PAPP-A2, which promote insulin-like growth factor (IGF) activity in tissues. Conclusion: Stanniocalcin-1 is a novel proteinase inhibitor. Significance: Altered stanniocalcin-1 expression may affect IGF signaling in vivo under normal or pathological conditions.

Section: Stc1 Inhibits the Proteolytic Activity Of Papp-a -To Test Thesupporting

confidence: 87%

Stanniocalcin-1 Potently Inhibits the Proteolytic Activity of the Metalloproteinase Pregnancy-associated Plasma Protein-A

Kløverpris

Mikkelsen

Pedersen

et al. 2015

“…It has previously been shown that 10 of these form five intramolecular disulfide bonds, and that one residue is responsible for dimerization (38). These 11 cysteine residues are conserved in STC2, which contains three additional cysteines, Cys-120, Cys-197, and Cys-205 (Fig.…”

Section: Abilities Of Stc2 To Covalently Bind and Inhibit Papp-a And mentioning

confidence: 99%

Stanniocalcin-2 Inhibits Mammalian Growth by Proteolytic Inhibition of the Insulin-like Growth Factor Axis

Jepsen¹,

Kløverpris²,

Mikkelsen³

et al. 2015

126

125

Background:The biological function and biochemical activity of mammalian stanniocalcin-2 are unknown. Results: Stanniocalcin-2 inhibits proteolytic release of insulin-like growth factor (IGF), and its ability to cause growth retardation upon transgenic overexpression in mice depends on its proteinase inhibitory function. Conclusion: Stanniocalcin-2 is a novel component of the IGF axis. Significance: Altered stanniocalcin-2 expression may affect IGF signaling under pathological conditions.

“…A cytochrome c-type CXXCH motif is present rather than the typical HRM (45)(46)(47)(48). Further studies are also required to establish the physiological relevance of the apparent heme-mediated inhibition of the arginine transferase activity of R-transferase and of putative heme binding to stanniocalcin glycoprotein hormones (52)(53)(54). For DGCR8, heme may have a structural role, although a heme redox state dependence on RNA binding was proposed (50,51 …”

Section: Non-nr Heme Sensorsmentioning

confidence: 99%

“…Heme binding was proposed to occur at a CS (not CP) motif. However, it was also reported that this Cys forms a disulfide and does not bind heme (53,54) and that STC1 may operate a thiol/disulfide redox switch, as described above (54). HRM-containing heme sensors are summarized in Table 1.…”

Section: Cellular Homeostasismentioning

confidence: 99%

Heme Sensor Proteins

Girvan

Munro

2013

128

116

Heme is a prosthetic group best known for roles in oxygen transport, oxidative catalysis, and respiratory electron transport. Recent years have seen the roles of heme extended to sensors of gases such as O 2 and NO and cell redox state, and as mediators of cellular responses to changes in intracellular levels of these gases. The importance of heme is further evident from identification of proteins that bind heme reversibly, using it as a signal, e.g. to regulate gene expression in circadian rhythm pathways and control heme synthesis itself. In this minireview, we explore the current knowledge of the diverse roles of heme sensor proteins. Heme-responsive Proteins: Defining FeaturesHeme homeostasis is crucial. Free heme at Ͼ1 M is cytotoxic, mainly by producing reactive oxygen species. Iron intake accounts for only a small proportion of mammalian requirements, so iron recycling (particularly from heme) is critical (1). Tight regulation of heme synthesis/breakdown is needed. Heme regulates its own fate and controls several other biological processes. Heme-responsive proteins elicit cellular responses by binding/debinding heme or via changes in heme ligation (e.g. by gases) or redox state. They can be divided into two classes: nuclear receptor (NR) 2 hemoproteins and heme sensors with no NR function. Each heme-responsive protein has a heme regulatory motif (HRM), usually containing a CP motif (2). The Cys residue of the CP motif is an axial heme ligand. No other residues are conserved across the protein class. The wider relevance of the CP motif is unclear because other hemoproteins (e.g. prostaglandin E 2 synthase, chloroperoxidase, and some cytochromes P450) also have a CP motif. The properties of members of the two main classes are described below. NR HemoproteinsSeveral heme-binding proteins occur in the NR superfamily, which is the largest transcription factor superfamily (summarized in Table 1). NRs bind specific DNA motifs in response to small molecule signaling. They generally share conserved domain architecture, with a DNA-binding region containing two zinc fingers, a ligand-binding domain, and activation domains (3). Usually, ligand binding induces conformational changes that dissociate partner proteins, allowing DNA binding and/or changes to dimerization status or cellular localization that enable the protein to elicit a response. A subfamily of NRs binds heme at their ligand-binding domain and so act as heme sensors, as discussed below. Circadian Rhythm Heme SensorsCircadian rhythms are regulated by feedback loops at transcriptional/translational levels. Heme is critical in this process (4). In vertebrates, the expression of several day/night cycle genes, as well as Rev-erb␣, is controlled by binding a heterodimer of Clock (or NPAS2 (neuronal PAS domain protein 2)) and Bmal1 to their 5Ј-UTR, thus switching on transcription. Expression of Bmal1 and NPAS2/Clock is repressed in turn by binding of Rev-erb␣ to a homodimeric partner (5). Rev-erb␣ and homologs (Rev-erb␤ and E75, with the latter involved in inse...