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1. Allosteric Regulation of Rod Photoreceptor Phosphodiesterase 6 (PDE6) Elucidated by Chemical Cross-Linking and Quantitative Mass Spectrometry

Author:
Chu, Feixia; Hogan, Donna; Gupta, Richa; Gao, Xiong-Zhuo; Nguyen, Hieu T.; Cote, Rick H.
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3677-3689
ISSN:
0022-2836
Subject:
active sites; catalytic activity; cones (retina); crosslinking; cyclic GMP; enzymes; hydrolysis; ligands; mass spectrometry; mutation; protein subunits; retinal diseases
Abstract:
... Photoreceptor phosphodiesterase (PDE6) is the central effector enzyme in the visual excitation pathway in rod and cone photoreceptors. Its tight regulation is essential for the speed, sensitivity, recovery, and adaptation of visual signaling. The rod PDE6 holoenzyme (Pαβγ2) is composed of a catalytic heterodimer (Pαβ) that binds two inhibitory γ subunits. Each of the two catalytic subunits (Pα and ...
DOI:
10.1016/j.jmb.2019.07.035

2. A Nuclear Zip Code in SKS1 mRNA Promotes Its Slow Export, Nuclear Retention, and Degradation by the Nuclear Exosome/DRN in Saccharomyces cerevisiae

Author:
Das, Subhadeep; Biswas, Subir; Chaudhuri, Shouvik; Bhattacharyya, Arindam; Das, Biswadip
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3626-3646
ISSN:
0022-2836
Subject:
Saccharomyces cerevisiae; exosomes; gene expression; messenger RNA; open reading frames; physiological transport
Abstract:
... In Saccharomyces cerevisiae, a special class of mRNAs representing a subset of otherwise normal transcripts displays very slow export and an unusually long intra-nuclear dwell time. This prolonged nuclear retention leads to their rapid degradation in the nucleus by the nuclear exosome and DRN (Decay of RNA in the Nucleus) apparatus. We previously attributed their slow export to one or more hypothe ...
DOI:
10.1016/j.jmb.2019.07.005

3. Biologically Active Ultra-Simple Proteins Reveal Principles of Transmembrane Domain Interactions

Author:
Federman, Ross S.; Boguraev, Anna-Sophia; Heim, Erin N.; DiMaio, Daniel
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3753-3770
ISSN:
0022-2836
Subject:
amino acid sequences; amino acid substitution; erythropoietin; evolution; hydrophobicity; leucine; mice; oligomerization; platelet-derived growth factor; platelet-derived growth factor receptor beta; transmembrane proteins
Abstract:
... Specific interactions between the helical membrane-spanning domains of transmembrane proteins play central roles in the proper folding and oligomerization of these proteins. However, the relationship between the hydrophobic amino acid sequences of transmembrane domains and their functional interactions is in most cases unknown. Here, we use ultra-simple artificial proteins to systematically study ...
DOI:
10.1016/j.jmb.2019.07.009

4. Cytosolic N- and C-Termini of the Aspergillus nidulans FurE Transporter Contain Distinct Elements that Regulate by Long-Range Effects Function and Specificity

Author:
Papadaki, Georgia F.; Lambrinidis, George; Zamanos, Andreas; Mikros, Emmanuel; Diallinas, George
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3827-3844
ISSN:
0022-2836
Subject:
Aspergillus nidulans; allantoin; endocytosis; evolution; genetic analysis; lipids; molecular dynamics; pH; substrate specificity; transporters; uracil; uric acid
Abstract:
... FurE, a member of the NCS1 family, is an Aspergillus nidulans transporter specific for uracil, allantoin and uric acid. Recently, we showed that C- or N-terminally truncated FurE versions are blocked for endocytosis and surprisingly show modified substrate specificities. Bifluorescence complementation assays and genetic analyses supported the idea that C- and N-termini interact dynamically and thr ...
DOI:
10.1016/j.jmb.2019.07.013

5. Gaining Insights into the Function of Post-Translational Protein Modification Using Genome Engineering and Molecular Cell Biology

Author:
Schmidhauser, Meret; Renz, Peter F.; Tsikrika, Panagiota; Freimann, Remo; Wutz, Anton; Wrana, Jeffrey L.; Beyer, Tobias A.
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3920-3932
ISSN:
0022-2836
Subject:
CRISPR-Cas systems; antibody specificity; chemical inhibitors; cyclin-dependent kinase; embryonic stem cells; gene editing; genes; phosphorylation; post-translational modification; serine; transcription factors
Abstract:
... Modifications by kinases are a fast and reversible mechanism to diversify the function of the targeted proteins. The OCT4 transcription factor is essential for preimplantation development and pluripotency of embryonic stem cells (ESC), and its activity is tightly regulated by post-transcriptional modifications. Several phosphorylation sites have been identified by systemic approaches and their fun ...
DOI:
10.1016/j.jmb.2019.07.015

6. How B-DNA Dynamics Decipher Sequence-Selective Protein Recognition

Author:
Battistini, Federica; Hospital, Adam; Buitrago, Diana; Gallego, Diego; Dans, Pablo D.; Gelpí, Josep Lluis; Orozco, Modesto
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3845-3859
ISSN:
0022-2836
Subject:
B-DNA; deformation; models
Abstract:
... The rules governing sequence-specific DNA–protein recognition are under a long-standing debate regarding the prevalence of base versus shape readout mechanisms to explain sequence specificity and of the conformational selection versus induced fit binding paradigms to explain binding-related conformational changes in DNA. Using a combination of atomistic simulations on a subset of representative se ...
DOI:
10.1016/j.jmb.2019.07.021

7. Intestinal Gel-Forming Mucins Polymerize by Disulfide-Mediated Dimerization of D3 Domains

Author:
Javitt, Gabriel; Calvo, María Luisa Gómez; Albert, Lis; Reznik, Nava; Ilani, Tal; Diskin, Ron; Fass, Deborah
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3740-3752
ISSN:
0022-2836
Subject:
amino acids; blood coagulation factors; crystal structure; dimerization; disulfide bonds; hemostasis; hydrogels; intestinal microorganisms; intestinal mucosa; models; mucins; polymerization; polymers; respiratory system
Abstract:
... The mucin 2 glycoprotein assembles into a complex hydrogel that protects intestinal epithelia and houses the gut microbiome. A major step in mucin 2 assembly is further multimerization of preformed mucin dimers, thought to produce a honeycomb-like arrangement upon hydrogel expansion. Important open questions are how multiple mucin 2 dimers become covalently linked to one another and how mucin 2 mu ...
DOI:
10.1016/j.jmb.2019.07.018

8. Ligand Binding Site Structure Shapes Folding, Assembly and Degradation of Homomeric Protein Complexes

Author:
Abrusán, György; Marsh, Joseph A.
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3871-3888
ISSN:
0022-2836
Subject:
binding proteins; binding sites; chaperonins; computational methodology; evolution; ligands; stochastic processes
Abstract:
... Ligand binding site structure has profound consequences for the evolution of function of protein complexes, particularly in homomers—complexes comprising multiple copies of the same protein. Previously, we have shown that homomers with multichain binding sites (MBSs) are characterized by more conserved binding sites and quaternary structure, and qualitatively different allosteric pathways than hom ...
DOI:
10.1016/j.jmb.2019.07.014

9. Molecular Organization of Soluble Type III Secretion System Sorting Platform Complexes

Author:
Bernal, Ivonne; Börnicke, Jonathan; Heidemann, Johannes; Svergun, Dmitri; Horstmann, Julia A.; Erhardt, Marc; Tuukkanen, Anne; Uetrecht, Charlotte; Kolbe, Michael
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3787-3803
ISSN:
0022-2836
Subject:
Gram-negative bacteria; Salmonella Typhimurium; adenosinetriphosphatase; mass spectrometry; pods; secretion; small-angle X-ray scattering; solubility; stoichiometry; tomography; type III secretion system
Abstract:
... Many medically relevant Gram‐negative bacteria use the type III secretion system (T3SS) to translocate effector proteins into the host for their invasion and intracellular survival. A multi-protein complex located at the cytosolic interface of the T3SS is proposed to act as a sorting platform by selecting and targeting substrates for secretion through the system. However, the precise stoichiometry ...
DOI:
10.1016/j.jmb.2019.07.004

10. Nol9 Is a Spatial Regulator for the Human ITS2 Pre-rRNA Endonuclease–Kinase Complex

Author:
Gordon, Jacob; Pillon, Monica C.; Stanley, Robin E.
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3771-3786
ISSN:
0022-2836
Subject:
catalytic activity; enzymes; humans; image analysis; internal transcribed spacers; motor neurons; phosphorylation; proteome; ribosomal RNA; ribosomes; translation (genetics)
Abstract:
... The ribosome plays a universal role in translating the cellular proteome. Defects in the ribosome assembly factor Las1L are associated with congenital lethal motor neuron disease and X-linked intellectual disability disorders, yet its role in processing precursor ribosomal RNA (pre-rRNA) is largely unclear. The Las1L endoribonuclease associates with the Nol9 polynucleotide kinase to form the inter ...
DOI:
10.1016/j.jmb.2019.07.007

11. Non-catalytic Binding Sites Induce Weaker Long-Range Evolutionary Rate Gradients than Catalytic Sites in Enzymes

Author:
Sharir-Ivry, Avital; Xia, Yu
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3860-3870
ISSN:
0022-2836
Subject:
active sites; binding sites; catalytic activity; enzymes; ligands; protein-protein interactions; proteins; solvents
Abstract:
... Enzymes exhibit a strong long-range evolutionary constraint that extends from their catalytic site and affects even distant sites, where site-specific evolutionary rate increases monotonically with distance. While protein–protein sites in enzymes were previously shown to induce only a weak conservation gradient, a comprehensive relationship between different types of functional sites in proteins a ...
DOI:
10.1016/j.jmb.2019.07.019

12. Observation of Continuous Contraction and a Metastable Misfolded State during the Collapse and Folding of a Small Protein

Author:
Bhatia, Sandhya; Krishnamoorthy, G.; Dhar, Deepak; Udgaonkar, Jayant B.
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3814-3826
ISSN:
0022-2836
Subject:
Gibbs free energy; activation energy; amino acid sequences; energy transfer; evolution; fluorescence; light intensity; models; polymers; polypeptides; protein folding
Abstract:
... To obtain proper insight into how structure develops during a protein folding reaction, it is necessary to understand the nature and mechanism of the polypeptide chain collapse reaction, which marks the initiation of folding. Here, the time-resolved fluorescence resonance energy transfer technique, in which the decay of the fluorescence light intensity with time is used to determine the time evolu ...
DOI:
10.1016/j.jmb.2019.07.024

13. On the Allosteric Effect of nsSNPs and the Emerging Importance of Allosteric Polymorphism

Author:
Tee, Wei-Ven; Guarnera, Enrico; Berezovsky, Igor N.
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3933-3942
ISSN:
0022-2836
Subject:
NADP-glucose-6-phosphate dehydrogenase; amino acid sequences; case studies; humans; mechanical models; phenotype; proteins; single nucleotide polymorphism; transferases
Abstract:
... The molecular mechanisms of pathological non-synonymous single-nucleotide polymorphisms are still the object of intensive research. To this end, we explore here whether non-synonymous single-nucleotide polymorphisms can work via allosteric mechanisms. Using structure-based statistical mechanical model of allostery and analyzing energetics of the effects of mutations in a set of 27 proteins with at ...
DOI:
10.1016/j.jmb.2019.07.012

14. Organization of Farnesylated, Carboxymethylated KRAS4B on Membranes

Author:
Barklis, Eric; Stephen, Andrew G.; Staubus, August O.; Barklis, Robin Lid; Alfadhli, Ayna
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3706-3717
ISSN:
0022-2836
Subject:
catalytic activity; cell membranes; humans; lipids; mutation; nanoparticles; neoplasms; post-translational modification; proteins
Abstract:
... Mutations of the Ras proteins HRAS, KRAS4A, KRAS4B, and NRAS are associated with a high percentage of all human cancers. The proteins are composed of highly homologous N-terminal catalytic or globular domains, plus C-terminal hypervariable regions (HVRs). Post-translational modifications of all RAS HVRs helps target RAS proteins to cellular membrane locations where they perform their signaling fun ...
DOI:
10.1016/j.jmb.2019.07.025

15. Phosphorylation of USP15 and USP4 Regulates Localization and Spliceosomal Deubiquitination

Author:
Das, Tanuza; Kim, Eunice EunKyeong; Song, Eun Joo
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3900-3912
ISSN:
0022-2836
Subject:
cyclin-dependent kinase; enzyme activity; enzyme inhibitors; fractionation; humans; mass spectrometry; phosphorylation; post-translational modification; sequence homology; spliceosomes; ubiquitinyl hydrolase 1
Abstract:
... Deubiquitinating enzymes have key roles in diverse cellular processes whose enzymatic activities are regulated by different mechanisms including post-translational modification. Here, we show that USP15 is phosphorylated, and its localization and activity are dependent on the phosphorylation status. Nuclear-cytoplasmic fractionation and mass spectrometric analysis revealed that Thr149 and Thr219 o ...
DOI:
10.1016/j.jmb.2019.07.023

16. Pyruvate Kinase Regulates the Pentose-Phosphate Pathway in Response to Hypoxia in Mycobacterium tuberculosis

Author:
Zhong, Wenhe; Guo, Jingjing; Cui, Liang; Chionh, Yok Hian; Li, Kuohan; El Sahili, Abbas; Cai, Qixu; Yuan, Meng; Michels, Paul A.M.; Fothergill-Gilmore, Linda A.; Walkinshaw, Malcolm D.; Mu, Yuguang; Lescar, Julien; Dedon, Peter C.
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3690-3705
ISSN:
0022-2836
Subject:
Mycobacterium tuberculosis; binding sites; carbon; crystal structure; enzyme activity; glucose 6-phosphate; glycolysis; hypoxia; metabolome; pentose phosphate cycle; pentoses; pyruvate kinase; ribose
Abstract:
... In response to the stress of infection, Mycobacterium tuberculosis (Mtb) reprograms its metabolism to accommodate nutrient and energetic demands in a changing environment. Pyruvate kinase (PYK) is an essential glycolytic enzyme in the phosphoenolpyruvate–pyruvate–oxaloacetate node that is a central switch point for carbon flux distribution. Here we show that the competitive binding of pentose mono ...
DOI:
10.1016/j.jmb.2019.07.033

17. Recruitment of Histone Methyltransferase Ehmt1 to Foxp3 TSDR Counteracts Differentiation of Induced Regulatory T Cells

Author:
Karl, Martin; Sommer, Christian; Gabriel, Christian H.; Hecklau, Katharina; Venzke, Melanie; Hennig, Anna Floriane; Radbruch, Andreas; Selbach, Matthias; Baumgrass, Ria
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3606-3625
ISSN:
0022-2836
Subject:
DNA; T-lymphocytes; epigenetics; gene editing; genes; histones; mass spectrometry; methyltransferases; transcription factors
Abstract:
... Differentiation toward CD4+ regulatory T (Treg) cells is essentially dependent on an epigenetic program at Treg signature genes, which involves remodeling of the Treg-specific demethylated regions (TSDRs). In particular, the epigenetic status of the conserved non-coding sequence 2 of Foxp3 (Foxp3 TSDR) determines expression stability of the master transcription factor and thus Treg lineage identit ...
DOI:
10.1016/j.jmb.2019.07.031

18. Structural Evidence for an Octameric Ring Arrangement of SARM1

Author:
Sporny, Michael; Guez-Haddad, Julia; Lebendiker, Mario; Ulisse, Valeria; Volf, Allison; Mim, Carsten; Isupov, Michail N.; Opatowsky, Yarden
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3591-3605
ISSN:
0022-2836
Subject:
adenosine diphosphate; animal injuries; apoptosis; brain; crystal structure; cultured cells; drug development; drugs; electron microscopy; electrostatic interactions; epitopes; hydrophobicity; mutation; oligomerization; protein subunits; proteins; ribose; spinal cord; therapeutics
Abstract:
... SARM1 induces axonal degeneration in response to various insults and is therefore considered an attractive drug target for the treatment of neuro-degenerative diseases as well as for brain and spinal cord injuries. SARM1 activity depends on the integrity of the protein's SAM domains, as well as on the enzymatic conversion of NAD+ to ADPR (ADP Ribose) products by the SARM1's TIR domain. Therefore, ...
DOI:
10.1016/j.jmb.2019.06.030

19. Structural Insights into α-Synuclein Fibril Polymorphism: Effects of Parkinson's Disease-Related C-Terminal Truncations

Author:
Ni, Xiaodan; McGlinchey, Ryan P.; Jiang, Jiansen; Lee, Jennifer C.
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3913-3919
ISSN:
0022-2836
Subject:
Lewy bodies; Parkinson disease; amyloid; cryo-electron microscopy; pathogenesis; proteinases
Abstract:
... Lewy bodies, hallmarks of Parkinson's disease, contain C-terminally truncated (ΔC) α-synuclein (α-syn). Here, we report fibril structures of three N-terminally acetylated (Ac) α-syn constructs, Ac1–140, Ac1–122, and Ac1–103, solved by cryoelectron microscopy. Both ΔC-α-syn variants exhibited faster aggregation kinetics, and Ac1–103 fibrils efficiently seeded the full-length protein, highlighting t ...
DOI:
10.1016/j.jmb.2019.07.001

20. Structure and Function Characterization of the a1a2 Motifs of Streptococcus pyogenes M Protein in Human Plasminogen Binding

Author:
Quek, Adam J.H.; Mazzitelli, Blake A.; Wu, Guojie; Leung, Eleanor W.W.; Caradoc-Davies, Tom T.; Lloyd, Gordon J.; Jeevarajah, Devadharshini; Conroy, Paul J.; Sanderson-Smith, Martina; Yuan, Yue; Ayinuola, Yetunde A.; Castellino, Francis J.; Whisstock, James C.; Law, Ruby H.P.
Source:
Journal of molecular biology 2019 v.431 no.19 pp. 3804-3813
ISSN:
0022-2836
Subject:
Streptococcus pyogenes; crystal structure; humans; lysine; mutagenesis; pathogens; peptides; plasminogen; proteolysis; virulence
Abstract:
... Plasminogen (Plg)-binding M protein (PAM) is a group A streptococcal cell surface receptor that is crucial for bacterial virulence. Previous studies revealed that, by binding to the kringle 2 (KR2) domain of host Plg, the pathogen attains a proteolytic microenvironment on the cell surface that facilitates its dissemination from the primary infection site. Each of the PAM molecules in their dimeric ...
DOI:
10.1016/j.jmb.2019.07.003