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J Biol Chem 2021 Apr 8:100652. Epub 2021 Apr 8.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232. Electronic address:

Processing of the amyloid precursor protein (APP) via the amyloidogenic pathway is associated with the etiology of Alzheimer's disease. The cleavage of APP by β-secretase to generate the transmembrane 99-residue C-terminal fragment (C99) and subsequent processing of C99 by γ-secretase to yield amyloid-β (Aβ) peptides are essential steps in this pathway. Biochemical evidence suggests amyloidogenic processing of C99 occurs in cholesterol- and sphingolipid-enriched liquid-ordered phase membrane rafts. Read More

Biochem Biophys Res Commun 2021 Apr 6;556:9-15. Epub 2021 Apr 6.

Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. Electronic address:

Lysosome-associated protein transmembrane 4α (LAPTM4α) is a four transmembrane-spanning protein primarily localized in endosomes and lysosomes and has several putative lysosomal targeting signals at its C-terminal cytoplasmic domain, including tyrosine-based motifs (YxxΦ) and PY motifs (L/PxxY). LAPTM4α has been previously shown to be ubiquitinated by the E3 ubiquitin ligase Nedd4-1 through binding to its PY motifs and sorted to lysosomes, however, the molecular mechanisms underlying the localization of LAPTM4α to endosomes/lysosomes have not yet been fully elucidated. In the present study, we show that LAPTM4α binds Nedd4-1 in a manner dependent on PY motifs, while the PY motifs and Nedd4-1 are not necessarily required for LAPTM4α ubiquitination. Read More

mBio 2021 04 6;12(2). Epub 2021 Apr 6.

Department of Biomolecular Health Sciences, Division of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands

At the intestinal host-microbe interface, the transmembrane mucin MUC1 can function as a physical barrier as well as a receptor for bacteria. MUC1 also influences epithelial cell morphology and receptor function. Various bacterial pathogens can exploit integrins to infect eukaryotic cells. Read More

Life Sci Alliance 2021 06 5;4(6). Epub 2021 Apr 5.

Department of Nutritional Physiology, Institute of Medical Nutrition, Tokushima University Graduate School, Tokushima, Japan.

Infection of certain influenza viruses is triggered when its HA is cleaved by host cell proteases such as proprotein convertases and type II transmembrane serine proteases (TTSP). HA with a monobasic motif is cleaved by trypsin-like proteases, including TMPRSS2 and HAT, whereas the multibasic motif found in high pathogenicity avian influenza HA is cleaved by furin, PC5/6, or MSPL. MSPL belongs to the TMPRSS family and preferentially cleaves [R/K]-K-K-R↓ sequences. Read More

J Med Genet 2021 Apr 2. Epub 2021 Apr 2.

APHP.Sorbonne Université, Département de Génétique, Groupe Hospitalier Pitié Salpêtrière et Hôpital Trousseau, Paris, Île-de-France, France.

De novo missense variants in encoding Kv10.1 are responsible for two clinically recognisable phenotypes: Temple-Baraitser syndrome (TBS) and Zimmermann-Laband syndrome (ZLS). The clinical overlap between these two syndromes suggests that they belong to a spectrum of -related encephalopathies. Read More

Int J Mol Sci 2021 Mar 29;22(7). Epub 2021 Mar 29.

Center for Arrhythmia Research, Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

The calcium pump (sarco/endoplasmic reticulum Ca-ATPase, SERCA) plays a major role in calcium homeostasis in muscle cells by clearing cytosolic Ca during muscle relaxation. Active Ca transport by SERCA involves the structural transition from a low-Ca affinity E2 state toward a high-Ca affinity E1 state of the pump. This structural transition is accompanied by the countertransport of protons to stabilize the negative charge and maintain the structural integrity of the transport sites and partially compensate for the positive charges of the two Ca ions passing through the membrane. Read More

Int J Mol Sci 2021 Mar 14;22(6). Epub 2021 Mar 14.

Departments of Biochemistry and Nutritional Sciences, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, Franklin-Wilkins Bldg, 150 Stamford St., London SE1 9NH, UK.

The human zinc transporter ZnT8 provides the granules of pancreatic β-cells with zinc (II) ions for assembly of insulin hexamers for storage. Until recently, the structure and function of human ZnTs have been modelled on the basis of the 3D structures of bacterial zinc exporters, which form homodimers with each monomer having six transmembrane α-helices harbouring the zinc transport site and a cytosolic domain with an α,β structure and additional zinc-binding sites. However, there are important differences in function as the bacterial proteins export an excess of zinc ions from the bacterial cytoplasm, whereas ZnT8 exports zinc ions into subcellular vesicles when there is no apparent excess of cytosolic zinc ions. Read More

Genome 2021 Mar 31. Epub 2021 Mar 31.

Sikkim University, 179229, Gangtok, Sikkim, India;

SARS-CoV-2 is mutating and creating divergent variants across the world. An in-depth investigation of the amino acid substitutions in the genomic signature of SARS-CoV-2 proteins is highly essential for understanding its host adaptation and infection biology. A total of 9587 SARS-CoV-2 structural protein sequences collected from 49 different countries are used to characterize protein-wise variants, substitution patterns (type and location), and major substitution changes. Read More

ACS Chem Neurosci 2021 Mar 31. Epub 2021 Mar 31.

Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, Arizona 85724, United States.

Neuropilin-1 (NRP-1) is a multifunctional transmembrane receptor for ligands that affect developmental axonal growth and angiogenesis. In addition to a role in cancer, NRP-1 is a reported entry point for several viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19). The furin cleavage product of SARS-CoV-2 Spike protein takes advantage of the vascular endothelial growth factor A (VEGF-A) binding site on NRP-1 which accommodates a polybasic stretch ending in a C-terminal arginine. Read More

J Struct Biol 2021 Mar 26;213(2):107729. Epub 2021 Mar 26.

Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom. Electronic address:

Bacterial type III secretion systems assemble the axial structures of both injectisomes and flagella. Injectisome type III secretion systems subsequently secrete effector proteins through their hollow needle into a host, requiring co-ordination. In the Salmonella enterica serovar Typhimurium SPI-2 injectisome, this switch is triggered by sensing the neutral pH of the host cytoplasm. Read More

Biochem J 2021 Mar 26. Epub 2021 Mar 26.

Macquarie University, Sydney, Australia.

Tau pathology initiates in defined brain regions and is known to spread along neuronal connections as symptoms progress in Alzheimer's disease (AD) and other tauopathies. This spread requires the release of tau from donor cells, but the underlying molecular mechanisms remained unknown. Here, we established the interactome of the C-terminal tail region of tau and identified syntaxin 8 (STX8) as a mediator of tau release from cells. Read More

Dev Comp Immunol 2021 Mar 23;121:104076. Epub 2021 Mar 23.

Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China; State Key Laboratory of Large Yellow Croaker Breeding, Ningde Fufa Fisheries Company Limited, Ningde, Fujian Province, 352103, China. Electronic address:

Mitochondrial antiviral signaling protein (MAVS) acts as an essential adaptor in host RIG-I-like receptors (RLRs) mediated antiviral signaling pathway. In the present study, two MAVS transcript variants, the typical form and a splicing variant, namely Lc-MAVS_tv1 and Lc-MAVS_tv2 were characterized in large yellow croaker (Larimichthys crocea). The putative Lc-MAVS_tv1 protein contains 512 aa, with an N-terminal CARD domain, a central proline-rich region, and a C-terminal transmembrane (TM) domain, whereas Lc-MAVS_tv2 contains 302 aa and lacks the C-terminal TM domain due to a premature stop in the 102 bp intron fragment insertion. Read More

J Biol Chem 2020 Dec 25;296:100221. Epub 2020 Dec 25.

Molecular Enzymology Group, University of Groningen, Groningen, the Netherlands. Electronic address:

Mammals rely on the oxidative flavin-containing monooxygenases (FMOs) to detoxify numerous and potentially deleterious xenobiotics; this activity extends to many drugs, giving FMOs high pharmacological relevance. However, our knowledge regarding these membrane-bound enzymes has been greatly impeded by the lack of structural information. We anticipated that ancestral-sequence reconstruction could help us identify protein sequences that are more amenable to structural analysis. Read More

J Virol 2021 Mar 17. Epub 2021 Mar 17.

University of Luebeck, Institute of Virology and Cell Biology, Luebeck, Germany

Pestiviruses like bovine viral diarrhea virus (BVDV) belong to the family A distinctive feature of the is the importance of non-structural (NS) proteins for RNA genome replication and virus morphogenesis. For pestiviruses, the NS2 protease-mediated release of NS3 is essential for RNA replication, whereas uncleaved NS2-3 is indispensable for producing viral progeny. Accordingly, in the pestiviral life cycle the switch from RNA replication to virion morphogenesis is temporally regulated by the extent of NS2-3 cleavage, which is catalyzed by the NS2 autoprotease. Read More

Endocrinology 2021 Mar 8. Epub 2021 Mar 8.

Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai.

The TSH receptor is a GPCR Group A family member with seven transmembrane helices. We generated three new models of its entire transmembrane region using a 600 ns molecular simulation. The simulation started from our previously published model which we have now revised by also modeling the intracellular loops and the C-terminal tail, adding internal waters and embedding it into a lipid bilayer with a water layer and with ions added to complete the system. Read More

J Neurosci 2021 Mar 4. Epub 2021 Mar 4.

Dept. of Neuroscience, University of Wisconsin-Madison.

Synaptophysin (syp) is a major integral membrane protein of secretory vesicles. Previous work has demonstrated functions for syp in synaptic vesicle cycling, endocytosis, and synaptic plasticity, but the role of syp in the process of membrane fusion during Ca-triggered exocytosis remains poorly understood. Furthermore, although syp resides on both large dense-core and small synaptic vesicles, its role in dense-core vesicle function has received less attention compared to synaptic vesicle function. Read More

Molecules 2021 Feb 26;26(5). Epub 2021 Feb 26.

Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Jülich, D-52425 Jülich, Germany.

The translocator protein (TSPO) is a 18kDa transmembrane protein, ubiquitously present in human mitochondria. It is overexpressed in tumor cells and at the sites of neuroinflammation, thus representing an important biomarker, as well as a promising drug target. In mammalian TSPO, there are cholesterol-binding motifs, as well as a binding cavity able to accommodate different chemical compounds. Read More

Protein Sci 2021 May 12;30(5):1072-1080. Epub 2021 Mar 12.

Department of Chemistry and Biochemistry, Southern Illinois University Carbondale, Carbondale, Illinois, USA.

Mitochondrial outer membrane permeabilization, which is a critical step in apoptosis, is initiated upon transmembrane insertion of the C-terminal α-helix (α9) of the proapoptotic Bcl-2 family protein BAX. The isolated α9 fragment (residues 173-192) is also competent to disrupt model membranes, and the structures of its membrane-associated oligomers are of interest in understanding the potential roles of this sequence in apoptosis. Here, we used ultrafast two-dimensional infrared (2D IR) spectroscopy, thioflavin T binding, and transmission electron microscopy to show that the synthetic BAX α9 peptide (α9p) forms amyloid aggregates in aqueous environments and on the surfaces of anionic small unilamellar vesicles. Read More

J Virol 2021 Feb 24. Epub 2021 Feb 24.

Microbiology and Molecular Biology Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, India

Holins are bacteriophage-encoded small transmembrane proteins that determine the phage infection cycle duration by forming non-specific holes in the host cell membrane at a specific time post-infection. Thus, Holins are also termed as "Protein clocks". Holins have one or more transmembrane domains, and a charged C-terminal region, which, although conserved among Holins, has not yet been examined in detail. Read More

Mol Biol Cell 2021 Apr 24;32(8):645-663. Epub 2021 Feb 24.

Department of Integrated Biosciences, University of Tokyo, Kashiwa, Chiba 277-8562, Japan.

Autophagy is a cellular degradation system widely conserved among eukaryotes. During autophagy, cytoplasmic materials fated for degradation are compartmentalized in double membrane-bound organelles called autophagosomes. After fusing with the vacuole, their inner membrane-bound structures are released into the vacuolar lumen to become autophagic bodies and eventually degraded by vacuolar hydrolases. Read More

J Bacteriol 2021 Feb 22. Epub 2021 Feb 22.

Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.

The MS ring is a part of the flagellar basal body and formed by 34 subunits of FliF, which consists of a large periplasmic region and two transmembrane segments connected to the N- and C-terminal regions facing the cytoplasm. A cytoplasmic protein, FlhF, which determines the position and number of the basal body, supports MS ring formation in the membrane in species. In this study, we constructed FliF deletion mutants that lack 30 or 50 residues from the N-terminus (ΔN30 and ΔN50), and 83 (ΔC83) or 110 residues (ΔC110) at the C-terminus. Read More

J Biol Chem 2021 Feb 18:100441. Epub 2021 Feb 18.

Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125. Electronic address:

The targeting and insertion of tail-anchored (TA) integral membrane proteins (IMP) into the correct membrane is critical for cellular homeostasis. The fungal protein Sgt2, and its human homolog SGTA, is the entry point for clients to the Guided Entry of Tail-anchored protein (GET) pathway, which targets ER-bound TA IMPs. Consisting of three structurally independent domains, the C-terminus of Sgt2 binds to the hydrophobic transmembrane domain (TMD) of clients. Read More

Hematol Oncol Stem Cell Ther 2021 Feb 11. Epub 2021 Feb 11.

Center for Genetics and Inherited Diseases, Taibah University Almadinah Almunawwarah, Medina, Saudi Arabia. Electronic address:

Glanzmann's thrombasthenia (GT) is an autosomal recessive congenital bleeding disorder of platelet aggregation. Mutations in ITGA2B and ITGB3 genes result in quantitative and/or qualitative abnormalities of the glycoprotein receptor complex IIb/IIIa (integrin αIIbβ3), which in turn impairs platelet aggregation and lead to GT. In this study, whole genome single nucleotide polymorphism (SNP) genotyping as well as whole exome sequencing was performed in a large family segregating GT. Read More

Exp Eye Res 2021 Apr 14;205:108497. Epub 2021 Feb 14.

Center of Anatomy and Cell Biology, Orphan Disease Genetics Group, Medical University of Vienna, Vienna, Austria.

Nanophthalmos-4 is a rare autosomal dominant disorder caused by two known variations in TMEM98. An Austrian Caucasian pedigree was identified suffering from nanophthalmos and late onset angle-closure glaucoma and premature loss of visual acuity. Whole exome sequencing identified segregation of a c. Read More

J Cell Sci 2021 Mar 26;134(6). Epub 2021 Mar 26.

Bateson Centre and Department of Biomedical Science, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, UK.

In vertebrate photoreceptors, opsins are highly concentrated in a morphologically distinct ciliary compartment known as the outer segment (OS). Opsin is synthesized in the cell body and transported to the OS at a remarkable rate of 100 to 1000 molecules per second. Opsin transport defects contribute to photoreceptor loss and blindness in human ciliopathies. Read More

Biophys J 2021 Feb 12. Epub 2021 Feb 12.

Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, United Kingdom; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom. Electronic address:

Piezo1 is a mechanosensitive channel involved in many cellular functions and responsible for sensing shear stress and pressure forces in cells. Piezo1 has a unique trilobed topology with a curved membrane region in the closed state. It has been suggested that upon activation Piezo1 adopts a flattened conformation, but the molecular and structural changes underpinning the Piezo1 gating and opening mechanisms and how the channel senses forces in the membrane remain elusive. Read More

J Hum Genet 2021 Feb 12. Epub 2021 Feb 12.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

FGFR3 encodes a transmembrane receptor tyrosine kinase that has six autophosphorylation sites of tyrosine. Among them, Y770 is a negative regulatory site for the downstream signaling of FGFR3. Constitutive active mutations in FGFR3 are involved in human developmental disorders including familial acanthosis nigricans, an autosomal dominant disorder characterized by general hyperpigmentation with mild acanthosis of the epidermis. Read More

Protein Sci 2021 Apr 2;30(4):855-872. Epub 2021 Mar 2.

Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.

Leucine Zipper EF-hand containing transmembrane protein-1 (LETM1) is an inner mitochondrial membrane protein that mediates mitochondrial calcium (Ca )/proton exchange. The matrix residing carboxyl (C)-terminal domain contains a sequence identifiable EF-hand motif (EF1) that is highly conserved among orthologues. Deletion of EF1 abrogates LETM1 mediated mitochondrial Ca flux, highlighting the requirement of EF1 for LETM1 function. Read More

mBio 2021 02 9;12(1). Epub 2021 Feb 9.

Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA

Diversion of the -containing vacuole (LCV) from the host endosomal-lysosomal degradation pathway is one of the main virulence features essential for manifestation of Legionnaires' pneumonia. Many of the ∼350 Dot/Icm-injected effectors identified in have been shown to interfere with various host pathways and processes, but no effector has ever been identified to be indispensable for lysosomal evasion. While most single effector mutants of do not exhibit a defective phenotype within macrophages, we show that the MavE effector is essential for intracellular growth of in human monocyte-derived macrophages (hMDMs) and amoebae and for intrapulmonary proliferation in mice. Read More

Int J Biol Macromol 2021 Apr 4;175:131-139. Epub 2021 Feb 4.

Department of Biophysics, Bose Institute, Kolkata 700 054, India. Electronic address:

One of the most crucial characteristic traits of Envelope (E) proteins in the severe acute respiratory syndrome SARS-CoV-1 and NCOVID19 viruses is their membrane-associated oligomerization led ion channel activity, virion assembly, and replication. NMR spectroscopic structural studies of envelope proteins from both the SARS CoV-1/2 reveal that this protein assembles into a homopentamer. Proof of concept studies via truncation mutants on either transmembrane (VFLLV), glycosylation motif (CACCN), hydrophobic helical bundle (PVYVY) as well as replacing C-terminal "DLLV" segments or point mutants such as S68, E69 residues with cysteine have significantly reduced viral titers of SARS-CoV-1. Read More