Analysis of the MCTP Amino Acid Sequence Reveals the Conservation of Putative Calcium- and Lipid-Binding Pockets Within the C2 Domains In Silico

Téllez-Arreola, José Luis; Martı́nez-Torres, Ataúlfo; Flores-Morán, Adriana; J, Lázaro-Guevara; Estrada-Mondragón, Argel

doi:10.1007/s00239-022-10057-1

Cited by 3 publications

(5 citation statements)

References 66 publications

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“…To our knowledge, this is the first study to combine evolutionary and structural modeling to study conservation of a membrane-binding electrostatic surface among a family of C2 domain proteins. Typical prior approaches address C2 domain evolutionary relationships at the sequence level to determine key consensus motifs and/or identify novel C2 domain relatives beyond the conventional classification (Craxton 2010; D. Zhang & Aravind 2010; Farrell et al 2012; D. Zhang & Aravind 2012; Tellez-Arreola et al 2022). Several studies have observed that Ca 2+ switches the electrostatic profile of many C2 domains from negative to positive, beginning with the seminal work of Murray and Honig (Murray & Honig 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Zhang & Aravind 2010;Farrell et al 2012;D. Zhang & Aravind 2012;Tellez-Arreola et al 2022). Several studies have observed that Ca 2+ switches the electrostatic profile of many C2 domains from negative to positive, beginning with the seminal work of Murray and Honig (Murray & Honig 2002).…”

Section: Usefulness Of This Approach To Studying Protein-membrane Int...mentioning

confidence: 99%

“…Slp family proteins are closely evolutionarily related to synaptotagmins, rabphilins, and Doc2b proteins, all of which contain tandem C2 domains belonging to the protein kinase C-type family (PKC-C2) (M. Rickman et al 2004;Craxton 2010;D. Zhang & Aravind 2010;Tellez-Arreola et al 2022). This family of C2 domains is typically characterized by Ca 2+ -dependent membrane binding, and many but not all synaptotagmins as well as rabphilins and Doc2b C2 domains bind membranes in a Ca 2+ -dependent manner (D.…”

Section: Sequence Conservation Among Slp Proteins and Relativesmentioning

confidence: 99%

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A Conserved Electrostatic Membrane-Binding Surface in Synaptotagmin-Like Proteins Revealed Using Molecular Phylogenetic Analysis and Homology Modeling

Chon

Tran

Miller

et al. 2023

Preprint

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Protein structure prediction has emerged as a core technology for understanding biomolecules and their interactions. Here, we combine homology-based structure prediction with molecular phylogenetic analysis to study the evolution of electrostatic membrane binding among vertebrate synaptotagmin-like proteins (Slps). Slp family proteins play key roles in the membrane trafficking of large dense-core secretory vesicles. Our previous experimental and computational study found that the C2A domain of Slp-4 (also called granuphilin) binds with high affinity to anionic phospholipids in the cytoplasmic leaflet of the plasma membrane through a large electropositive protein surface centered on a cluster of phosphoinositide-binding lysine residues. Because the polybasic surface contributes greatly to Slp-4 C2A domain membrane binding, we hypothesized that the net charge on the large electropositive surface might be evolutionarily conserved. To test this hypothesis, the known C2A sequences of Slp-4 among vertebrates were organized by class (from mammalia to pisces) using molecular phylogenetic analysis. Consensus sequences for each class were then identified and used to generate homology structures, from which Poisson-Boltzmann electrostatic potentials were calculated. For comparison, homology structures and electrostatic potentials were also calculated for the five human Slp protein family members. The results demonstrate that the charge on the membrane-binding surface is highly conserved throughout the evolution of Slp-4, and more highly conserved than many individual residues in the mammalian Slp C2A domain family overall. Such molecular phylogenetic-driven computational analysis can help to describe the evolution of electrostatic interactions between proteins and membranes which are crucial for their function.

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Section: Discussionmentioning

confidence: 99%

Section: Usefulness Of This Approach To Studying Protein-membrane Int...mentioning

confidence: 99%

Section: Sequence Conservation Among Slp Proteins and Relativesmentioning

confidence: 99%

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A Conserved Electrostatic Membrane-Binding Surface in Synaptotagmin-Like Proteins Revealed Using Molecular Phylogenetic Analysis and Homology Modeling

Chon

Tran

Miller

et al. 2023

Preprint

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show abstract

“…To our knowledge, this is the first study to combine evolutionary and structural modeling to study conservation of a membrane‐binding electrostatic surface among a family of C2 domain proteins. Typical prior approaches address C2 domain evolutionary relationships at the sequence level to determine key consensus motifs and/or identify novel C2 domain relatives beyond the conventional classification (Craxton, 2010; Farrell et al, 2012; Tellez‐Arreola et al, 2022; Zhang & Aravind, 2010, 2012). Several studies have observed that Ca 2+ switches the electrostatic profile of many C2 domains from negative to positive, beginning with the seminal work of Murray and Honig (2002).…”

Section: Discussionmentioning

confidence: 99%

A conserved electrostatic membrane‐binding surface in synaptotagmin‐like proteins revealed using molecular phylogenetic analysis and homology modeling

Chon,

Tran,

Miller

et al. 2023

Protein Science

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Protein structure prediction has emerged as a core technology for understanding biomolecules and their interactions. Here, we combine homology‐based structure prediction with molecular phylogenetic analysis to study the evolution of electrostatic membrane binding among the vertebrate synaptotagmin‐like protein (Slp) family. Slp family proteins play key roles in the membrane trafficking of large dense‐core secretory vesicles. Our previous experimental and computational study found that the C2A domain of Slp‐4 (also called granuphilin) binds with high affinity to anionic phospholipids in the cytoplasmic leaflet of the plasma membrane through a large positively charged protein surface centered on a cluster of phosphoinositide‐binding lysine residues. Because this surface contributes greatly to Slp‐4 C2A domain membrane binding, we hypothesized that the net charge on the surface might be evolutionarily conserved. To test this hypothesis, the known C2A sequences of Slp‐4 among vertebrates were organized by class (from mammalia to pisces) using molecular phylogenetic analysis. Consensus sequences for each class were then identified and used to generate homology structures, from which Poisson–Boltzmann electrostatic potentials were calculated. For comparison, homology structures and electrostatic potentials were also calculated for the five human Slp protein family members. The results demonstrate that the charge on the membrane‐binding surface is highly conserved throughout the evolution of Slp‐4, and more highly conserved than many individual residues among the human Slp family paralogs. Such molecular phylogenetic‐driven computational analysis can help to describe the evolution of electrostatic interactions between proteins and membranes which are crucial for their function.

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“…They are anchored into the ER and promote the release of synaptic vesicles [54]. While the C2 domains bind calcium and possess lipid binding signature sequences, their ability to bind membranes has not yet been demonstrated [52,53].…”

Section: The C2 Domains Are the Most Common Tmmr Modulementioning

confidence: 99%

Transmembrane Membrane Readers form a Novel Class of Proteins That Include Peripheral Phosphoinositide Recognition Domains and Viral Spikes

Overduin

Tran

Eekels³

et al. 2022

Membranes

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Membrane proteins are broadly classified as transmembrane (TM) or peripheral, with functions that pertain to only a single bilayer at a given time. Here, we explicate a class of proteins that contain both transmembrane and peripheral domains, which we dub transmembrane membrane readers (TMMRs). Their transmembrane and peripheral elements anchor them to one bilayer and reversibly attach them to another section of bilayer, respectively, positioning them to tether and fuse membranes while recognizing signals such as phosphoinositides (PIs) and modifying lipid chemistries in proximity to their transmembrane domains. Here, we analyze full-length models from AlphaFold2 and Rosetta, as well as structures from nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography, using the Membrane Optimal Docking Area (MODA) program to map their membrane-binding surfaces. Eukaryotic TMMRs include phospholipid-binding C1, C2, CRAL-TRIO, FYVE, GRAM, GTPase, MATH, PDZ, PH, PX, SMP, StART and WD domains within proteins including protrudin, sorting nexins and synaptotagmins. The spike proteins of SARS-CoV-2 as well as other viruses are also TMMRs, seeing as they are anchored into the viral membrane while mediating fusion with host cell membranes. As such, TMMRs have key roles in cell biology and membrane trafficking, and include drug targets for diseases such as COVID-19.

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Analysis of the MCTP Amino Acid Sequence Reveals the Conservation of Putative Calcium- and Lipid-Binding Pockets Within the C2 Domains In Silico

Cited by 3 publications

References 66 publications

A Conserved Electrostatic Membrane-Binding Surface in Synaptotagmin-Like Proteins Revealed Using Molecular Phylogenetic Analysis and Homology Modeling

A Conserved Electrostatic Membrane-Binding Surface in Synaptotagmin-Like Proteins Revealed Using Molecular Phylogenetic Analysis and Homology Modeling

A conserved electrostatic membrane‐binding surface in synaptotagmin‐like proteins revealed using molecular phylogenetic analysis and homology modeling

Transmembrane Membrane Readers form a Novel Class of Proteins That Include Peripheral Phosphoinositide Recognition Domains and Viral Spikes

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