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2021 ◽  
Vol 154 (1) ◽  
Author(s):  
Zhuyuan Chen ◽  
Sheng Lin ◽  
Tianze Xie ◽  
Jin-Ming Lin ◽  
Cecilia M. Canessa

Proton-gated ion channels conduct mainly Na+ to induce postsynaptic membrane depolarization. Finding the determinants of ion selectivity requires knowledge of the pore structure in the open conformation, but such information is not yet available. Here, the open conformation of the hASIC1a channel was computationally modeled, and functional effects of pore mutations were analyzed in light of the predicted structures. The open pore structure shows two constrictions of similar diameter formed by the backbone of the GAS belt and, right beneath it, by the side chains of H28 from the reentrant loop. Models of nonselective mutant channels, but not those that maintain ion selectivity, predict enlargement of the GAS belt, suggesting that this motif is quite flexible and that the loss of stabilizing interactions in the central pore leads to changes in size/shape of the belt. Our results are consistent with the “close-fit” mechanism governing selectivity of hASIC1a, wherein the backbone of the GAS substitutes at least part of the hydration shell of a permeant ion to enable crossing the pore constriction.


2021 ◽  
Author(s):  
Zhejian Ji ◽  
Hao Li ◽  
Daniele Peterle ◽  
Joao A Paulo ◽  
Scott B Ficarro ◽  
...  

The hexameric Cdc48 ATPase (p97 or VCP in mammals) cooperates with its cofactor Ufd1/Npl4 to extract polyubiquitinated proteins from membranes or macromolecular complexes for degradation by the proteasome. Here, we clarify how the Cdc48 complex unfolds its substrates and translocates polypeptides with branchpoints. The Cdc48 complex recognizes primarily polyubiquitin chains, rather than the attached substrate. Cdc48 and Ufd1/Npl4 cooperatively bind the polyubiquitin chain, resulting in the unfolding of one ubiquitin molecule (initiator). Next, the ATPase pulls on the initiator ubiquitin and moves all ubiquitin molecules linked to its C-terminus through the central pore of the hexameric double-ring, causing transient ubiquitin unfolding. When the ATPase reaches the isopeptide bond of the substrate, it can translocate and unfold both N- and C-terminal segments. Ubiquitins linked to the branchpoint of the initiator dissociate from Ufd1/Npl4 and move outside the central pore, resulting in the release of unfolded, polyubiquitinated substrate from Cdc48.


2021 ◽  
Vol 11 (2) ◽  
pp. 20200090
Author(s):  
Marie Michenkova ◽  
Sara Taki ◽  
Matthew C. Blosser ◽  
Hyea J. Hwang ◽  
Thomas Kowatz ◽  
...  

Carbon dioxide (CO 2 ) movement across cellular membranes is passive and governed by Fick's law of diffusion. Until recently, we believed that gases cross biological membranes exclusively by dissolving in and then diffusing through membrane lipid. However, the observation that some membranes are CO 2 impermeable led to the discovery of a gas molecule moving through a channel; namely, CO 2 diffusion through aquaporin-1 (AQP1). Later work demonstrated CO 2 diffusion through rhesus (Rh) proteins and NH 3 diffusion through both AQPs and Rh proteins. The tetrameric AQPs exhibit differential selectivity for CO 2 versus NH 3 versus H 2 O, reflecting physico-chemical differences among the small molecules as well as among the hydrophilic monomeric pores and hydrophobic central pores of various AQPs. Preliminary work suggests that NH 3 moves through the monomeric pores of AQP1, whereas CO 2 moves through both monomeric and central pores. Initial work on AQP5 indicates that it is possible to create a metal-binding site on the central pore's extracellular face, thereby blocking CO 2 movement. The trimeric Rh proteins have monomers with hydrophilic pores surrounding a hydrophobic central pore. Preliminary work on the bacterial Rh homologue AmtB suggests that gas can diffuse through the central pore and three sets of interfacial clefts between monomers. Finally, initial work indicates that CO 2 diffuses through the electrogenic Na/HCO 3 cotransporter NBCe1. At least in some cells, CO 2 -permeable proteins could provide important pathways for transmembrane CO 2 movements. Such pathways could be amenable to cellular regulation and could become valuable drug targets.


2020 ◽  
pp. jbc.RA120.014739 ◽  
Author(s):  
Vanessa Carvalho ◽  
Irfan Prabudiansyah ◽  
Lubomir Kovacik ◽  
Mohamed Chami ◽  
Roland Kieffer ◽  
...  

AAA+ proteases are degradation machines that use ATP hydrolysis to unfold protein substrates and translocate them through a central pore towards a degradation chamber. FtsH, a bacterial membrane-anchored AAA+ protease, plays a vital role in membrane protein quality control. How substrates reach the FtsH central pore is an open key question that is not resolved by the available atomic structures of cytoplasmic and periplasmic domains. In this work, we used both negative stain TEM and cryo-EM to determine 3D maps of the full-length Aquifex aeolicus FtsH protease. Unexpectedly, we observed that detergent solubilisation induces the formation of fully active FtsH dodecamers, which consist of two FtsH hexamers in a single detergent micelle. The striking tilted conformation of the cytosolic domain in the FtsH dodecamer visualized by negative stain TEM suggests a lateral substrate entrance between membrane and cytosolic domain. Such a substrate path was then resolved in the cryo-EM structure of the FtsH hexamer.  By mapping the available structural information and structure predictions for the transmembrane helices to the amino acid sequence we identified a linker of ~20 residues between the second transmembrane helix and the cytosolic domain.  This unique polypeptide appears to be highly flexible, and turned out to be essential for proper functioning of FtsH as its deletion fully eliminated the proteolytic activity of FtsH.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Matthew Faulkner ◽  
István Szabó ◽  
Samantha L. Weetman ◽  
Francois Sicard ◽  
Roland G. Huber ◽  
...  

Abstract Bacterial microcompartments (BMCs) are nanoscale proteinaceous organelles that encapsulate enzymes from the cytoplasm using an icosahedral protein shell that resembles viral capsids. Of particular interest are the carboxysomes (CBs), which sequester the CO2-fixing enzymes ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) to enhance carbon assimilation. The carboxysome shell serves as a semi-permeable barrier for passage of metabolites in and out of the carboxysome to enhance CO2 fixation. How the protein shell directs influx and efflux of molecules in an effective manner has remained elusive. Here we use molecular dynamics and umbrella sampling calculations to determine the free-energy profiles of the metabolic substrates, bicarbonate, CO2 and ribulose bisphosphate and the product 3-phosphoglycerate associated with their transition through the major carboxysome shell protein CcmK2. We elucidate the electrostatic charge-based permeability and key amino acid residues of CcmK2 functioning in mediating molecular transit through the central pore. Conformational changes of the loops forming the central pore may also be required for transit of specific metabolites. The importance of these in-silico findings is validated experimentally by site-directed mutagenesis of the key CcmK2 residue Serine 39. This study provides insight into the mechanism that mediates molecular transport through the shells of carboxysomes, applicable to other BMCs. It also offers a predictive approach to investigate and manipulate the shell permeability, with the intent of engineering BMC-based metabolic modules for new functions in synthetic biology.


Phytotaxa ◽  
2020 ◽  
Vol 458 (2) ◽  
pp. 173-181
Author(s):  
ALICIA MARQUES TORRES ◽  
MARCOS JOSÉ DA SILVA ◽  
WESLEY PATRÍCIO FREIRE DE SÁ CORDEIRO ◽  
SARAH MARIA ATHIÊ-SOUZA ◽  
MARGARETH FERREIRA DE SALES

Two new species, Phyllanthus itamarajuensis and P. tuberculatus (Phyllanthaceae), currently restricted to the Atlantic Forest of Bahia State, Brazil, are described and illustrated. Phyllanthus itamarajuensis is distinguished by having long styles (2–2.2 mm long) associated with subshrubby habit, discretely asymmetrical basal leaves, and anthers with vertical dehiscence. Phyllanthus tuberculatus is characterized by glabrous leaves, a long pistillate pedicel (18–20 mm long), flowers of both sexes 5-merous, disk of the staminate flowers with five obtriangular segments with tuberculated surfaces, each being separated by a deep recess, and each with a central pore, anthers with non-divergent thecae, and a patelliform pistillate disk. The systematic position of both new species is discussed, and comments are provided on their morphological relationships, geographic distribution, conservation status, environmental preferences, and phenology.


2020 ◽  
Author(s):  
Matthew Faulkner ◽  
István Szabó ◽  
Samantha L. Weetman ◽  
Francois Sicard ◽  
Roland G. Huber ◽  
...  

AbstractBacterial microcompartments (BMCs) are nanoscale proteinaceous organelles that encapsulate enzymes from the cytoplasm using an icosahedral protein shell that resembles viral capsids. Of particular interest are the carboxysomes (CBs), which sequester the CO2-fixing enzymes ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) to enhance carbon assimilation. The carboxysome shell serves as a semi-permeable barrier for passage of metabolites in and out of the carboxysome to enhance CO2 fixation. How the protein shell directs influx and efflux of molecules in an effective manner has remained elusive. Here we use molecular dynamics and umbrella sampling calculations to determine the free-energy profiles of the metabolic substrates, bicarbonate, CO2 and ribulose bisphosphate and the product 3-phosphoglycerate associated with their transition through the major carboxysome shell protein CcmK2. We elucidate the electrostatic charge-based permeability and key amino acid residues of CcmK2 functioning in mediating molecular transit through the central pore. Conformational changes of the loops forming the central pore may also be required for transit of specific metabolites. The importance of these in-silico findings is validated experimentally by site-directed mutagenesis of the key CcmK2 residue Serine 39. This study provides insight into the mechanism that mediates molecular transport through the shells of carboxysomes, applicable to other BMCs. It also offers a predictive approach to investigate and manipulate the shell permeability, with the intend of engineering BMC-based metabolic modules for new functions in synthetic biology.


2020 ◽  
Vol 35 (4) ◽  
Author(s):  
Javier Sánchez-Bernal ◽  
Mariano Ara-Martín ◽  
Isabel Abadías-Granado ◽  
Oriol Yélamos

Molluscum contagiosum (MC), a frequent viral infection, is generally easy to diagnose because of its characteristic clinical features. However, atypical presentations can be a diagnostic challenge for clinicians. Dermoscopy has helped in this cases by showing a characteristic dermoscopic pattern composed of a central pore or umbilication in conjunction with polylobular white to yellow amorphous structures, surrounded by linear or branched vessels (‘red crown”). However, additional dermoscopic patterns can be found. Herein we present two MC cases where rosettes were seen on dermoscopy


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