Abstract:IMPDH has a function in the retina, apparently independent of its enzymatic activity, mediated by retina-specific variants. This moonlighting activity may involve the posttranscriptional regulation of rhodopsin mRNA. The adRP mutation D226N has reduced binding to nucleic acids and reduced association with polyribosomes. If this mutation perturbs the biosynthesis of rhodopsin in some way, this would explain a link between IMPDH and the mechanism of retinal degeneration.
“…5B), readily explaining how guanine and adenine nucleotides stabilize the different conformations of the hinges, thereby inducing changes in the structure of AgIMPDH. Interestingly, several residues in AgIMPDH that correspond to missense mutations in HsIMPDH1 associated to retinopathies 14 lie within the linker regions and/or are directly involved in stabilizing the different conformations of the hinge bending residues (Supplementary Fig. 5), pointing to an important physiological role of the IMPDH conformational switch within cells.Figure 2The conformational switch of AgIMPDH.…”
Section: Resultsmentioning
confidence: 99%
“…12, 13 . In IMPDH, missense mutations within the Bateman domain of human isoform 1 (HsIMPDH1) are linked to Leber Congenital Amaurosis and Retinitis Pigmentosa 14 .…”
Section: Introductionmentioning
confidence: 99%
“…Thereby, the comparison of the high-resolution structures of the activated (in complex with ATP) and inhibited (in complex with either GDP 5 or a mixture of ATP/GDP) AgIMPDH defines the atomic and mechanistic details of a novel purine-nucleotide-controlled conformational switch that allosterically modulate the catalytic activity of eukaryotic IMPDHs. Remarkably, several residues in AgIMPDH that correspond to missense mutations in HsIMPDH1 associated to human retinopathies 14 map into the linker regions that connect the catalytic and Bateman domains and are directly involved in the stabilization of the different conformations that the hinge bending residues adopt. This observation is indicative of the potential physiological relevance of the IMPDH conformational switch.…”
Inosine-5′-monophosphate dehydrogenase (IMPDH) is an essential enzyme for nucleotide metabolism and cell proliferation. Despite IMPDH is the target of drugs with antiviral, immunosuppressive and antitumor activities, its physiological mechanisms of regulation remain largely unknown. Using the enzyme from the industrial fungus Ashbya gossypii, we demonstrate that the binding of adenine and guanine nucleotides to the canonical nucleotide binding sites of the regulatory Bateman domain induces different enzyme conformations with significantly distinct catalytic activities. Thereby, the comparison of their high-resolution structures defines the mechanistic and structural details of a nucleotide-controlled conformational switch that allosterically modulates the catalytic activity of eukaryotic IMPDHs. Remarkably, retinopathy-associated mutations lie within the mechanical hinges of the conformational change, highlighting its physiological relevance. Our results expand the mechanistic repertoire of Bateman domains and pave the road to new approaches targeting IMPDHs.
“…5B), readily explaining how guanine and adenine nucleotides stabilize the different conformations of the hinges, thereby inducing changes in the structure of AgIMPDH. Interestingly, several residues in AgIMPDH that correspond to missense mutations in HsIMPDH1 associated to retinopathies 14 lie within the linker regions and/or are directly involved in stabilizing the different conformations of the hinge bending residues (Supplementary Fig. 5), pointing to an important physiological role of the IMPDH conformational switch within cells.Figure 2The conformational switch of AgIMPDH.…”
Section: Resultsmentioning
confidence: 99%
“…12, 13 . In IMPDH, missense mutations within the Bateman domain of human isoform 1 (HsIMPDH1) are linked to Leber Congenital Amaurosis and Retinitis Pigmentosa 14 .…”
Section: Introductionmentioning
confidence: 99%
“…Thereby, the comparison of the high-resolution structures of the activated (in complex with ATP) and inhibited (in complex with either GDP 5 or a mixture of ATP/GDP) AgIMPDH defines the atomic and mechanistic details of a novel purine-nucleotide-controlled conformational switch that allosterically modulate the catalytic activity of eukaryotic IMPDHs. Remarkably, several residues in AgIMPDH that correspond to missense mutations in HsIMPDH1 associated to human retinopathies 14 map into the linker regions that connect the catalytic and Bateman domains and are directly involved in the stabilization of the different conformations that the hinge bending residues adopt. This observation is indicative of the potential physiological relevance of the IMPDH conformational switch.…”
Inosine-5′-monophosphate dehydrogenase (IMPDH) is an essential enzyme for nucleotide metabolism and cell proliferation. Despite IMPDH is the target of drugs with antiviral, immunosuppressive and antitumor activities, its physiological mechanisms of regulation remain largely unknown. Using the enzyme from the industrial fungus Ashbya gossypii, we demonstrate that the binding of adenine and guanine nucleotides to the canonical nucleotide binding sites of the regulatory Bateman domain induces different enzyme conformations with significantly distinct catalytic activities. Thereby, the comparison of their high-resolution structures defines the mechanistic and structural details of a nucleotide-controlled conformational switch that allosterically modulates the catalytic activity of eukaryotic IMPDHs. Remarkably, retinopathy-associated mutations lie within the mechanical hinges of the conformational change, highlighting its physiological relevance. Our results expand the mechanistic repertoire of Bateman domains and pave the road to new approaches targeting IMPDHs.
“…Moreover, DNA damage response could increase the activity of miRNAs involved in [60,61] and cell death genes transcription by TP53 [62], determining a possible role in retina degeneration. In the meantime, as already discussed, retinal cells could try to fight against induced stress, and one resistance mechanism could be represented by the improved maturation of the large ribosomal unit (LSU) [63] and by the increased polyribosome activity, showing a fundamental role in translation regulation of many retinal genes [64,65]. Detailed analysis of DE and DAS gene-involved pathways, with their possible impact on retinal dystrophies etiopathogenesis, is reported in Table 2.…”
Oxidative stress represents one of the principal inductors of lifestyle-related and genetic diseases. Among them, inherited retinal dystrophies, such as age-related macular degeneration and retinitis pigmentosa, are well known to be susceptible to oxidative stress. To better understand how high reactive oxygen species levels may be involved in retinal dystrophies onset and progression, we performed a whole RNA-Seq experiment. It consisted of a comparison of transcriptomes’ profiles among human retinal pigment epithelium cells exposed to the oxidant agent N-retinylidene-N-retinylethanolamine (A2E), considering two time points (3h and 6h) after the basal one. The treatment with A2E determined relevant differences in gene expression and splicing events, involving several new pathways probably related to retinal degeneration. We found 10 different clusters of pathways involving differentially expressed and differentially alternative spliced genes and highlighted the sub- pathways which could depict a more detailed scenario determined by the oxidative-stress-induced condition. In particular, regulation and/or alterations of angiogenesis, extracellular matrix integrity, isoprenoid-mediated reactions, physiological or pathological autophagy, cell-death induction and retinal cell rescue represented the most dysregulated pathways. Our results could represent an important step towards discovery of unclear molecular mechanisms linking oxidative stress and etiopathogenesis of retinal dystrophies.
“…The future promises further application of quaternary structure dynamics to drug discovery. Particularly intriguing are the metabolic enzymes, like pyruvate kinase and glyceraldehyde-3-phosphate dehydrogenase [45], which have alternate functions in alternate cellular compartments, or whose reversible polymerization is associated with cell cycle control, such as inosine monophosphate dehydrogenase and CTP synthase [46], the former of which is also associated with moonlighting functions [47–48]. …”
The morpheein model of allosteric regulation draws attention to proteins that can exist as an equilibrium of functionally distinct assemblies where: one subunit conformation assembles into one multimer; a different subunit conformation assembles into a different multimer; and the various multimers are in a dynamic equilibrium whose position can be modulated by ligands that bind to a multimer-specific ligand binding site. The case study of porphobilinogen synthase (PBGS) illustrates how such an equilibrium holds lessons for disease mechanisms, drug discovery, understanding drug side effects, and identifying proteins wherein drug discovery efforts might focus on quaternary structure dynamics. The morpheein model of allostery has been proposed as applicable for a wide assortment of disease-associated proteins (Selwood, T., Jaffe, E., (2012) Arch. Bioch. Biophys, 519:131–143). Herein we discuss quaternary structure dynamics aspects to drug discovery for the disease-associated putative morpheeins phenylalanine hydroxylase, HIV integrase, pyruvate kinase, and tumor necrosis factor α. Also highlighted is the quaternary structure equilibrium of transthyretin and successful drug discovery efforts focused on controlling its quaternary structure dynamics.
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