An early, novel arginine methylation of KCa3.1 attenuates subsequent T cell exhaustion.

T cell receptor (TCR) engagement initiates the activation process, and this signaling event is regulated in multifaceted ways. Nutrient availability in the immediate niche is one such mode of regulation . Here, we investigated how the availability of an essential amino acid methionine (Met) and TCR signaling might interplay in the earliest events of T cell activation to affect subsequent T cell fate and function.

Pathogenic variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease.

Troponin I (TnI) regulates thin filament activation and muscle contraction. Two isoforms, TnI-fast () and TnI-slow (), are predominantly expressed in fast- and slow-twitch myofibers, respectively. variants are a rare cause of arthrogryposis, whereas variants have not been conclusively established to cause skeletal myopathy.

Peptide-scFv antigen recognition domains effectively confer CAR T cell multiantigen specificity.

The emergence of immune escape is a significant roadblock to developing effective chimeric antigen receptor (CAR) T cell therapies against hematological malignancies, including acute myeloid leukemia (AML). Here, we demonstrate feasibility of targeting two antigens simultaneously by combining a GRP78-specific peptide antigen recognition domain with a CD123-specific scFv to generate a peptide-scFv bispecific antigen recognition domain (78.123).

Prediction of Kv11.1 potassium channel PAS-domain variants trafficking via machine learning.

Congenital long QT syndrome (LQTS) is characterized by a prolonged QT-interval on an electrocardiogram (ECG). An abnormal prolongation in the QT-interval increases the risk for fatal arrhythmias. Genetic variants in several different cardiac ion channel genes, including KCNH2, are known to cause LQTS.

Recent breakthroughs in computational structural biology harnessing the power of sequences and structures.

Recent advances in computational approaches and their integration into structural biology enable tackling increasingly complex questions. Here, we discuss several key areas, highlighting breakthroughs and remaining challenges. Theoretical modeling has provided tools to accurately predict and design protein structures on a scale currently difficult to achieve using experimental approaches.

An investigation of the YidC-mediated membrane insertion of Pf3 coat protein using molecular dynamics simulations.

YidC is a membrane protein that facilitates the insertion of newly synthesized proteins into lipid membranes. Through YidC, proteins are inserted into the lipid bilayer via the SecYEG-dependent complex. Additionally, YidC functions as a chaperone in protein folding processes.

Elucidating the molecular basis of spontaneous activation in an engineered mechanosensitive channel.

Mechanosensitive channel of large conductance (MscL) detects and responds to changes in the pressure profile of cellular membranes and transduces the mechanical energy into electrical and/or chemical signals. MscL can be activated using ultrasonic or chemical activation methods to improve the absorption of medicines and bioactive compounds into cells. However, re-engineering chemical signals such as pH change can trigger channel activation in MscL.

Modulation of P2X4 pore closure by magnesium, potassium, and ATP.

The P2X4 receptor plays a prominent role in cellular responses to extracellular ATP. Through classical all-atom molecular dynamics (MD) simulations totaling 24 μs we have investigated how metal-complexed ATP stabilizes the channel's open state and prevents its closing. We have identified two metal-binding sites, Mg and potassium K, one at the intersection of the three subunits in the ectodomain (MBS1) and the second one near the ATP-binding site (MBS2), similar to those characterized in Gulf Coast P2X.

Mechanistic Picture for Chemomechanical Coupling in a Bacterial Proton-Coupled Oligopeptide Transporter from Streptococcus Thermophilus.

Proton-coupled oligopeptide transporters (POTs) use the proton electrochemical gradient to transport peptides across the cell membrane. Despite the significant biological and biomedical relevance of these proteins, a detailed mechanistic picture for chemomechanical couplings involved in substrate/proton transport and protein structural changes is missing. Therefore, we performed microsecond-level molecular dynamics simulations of bacterial POT PepT, which shares ∼80% sequence identity with the human POT, PepT1, in the substrate-binding region.

Structural Changes beyond the EF-Hand Contribute to Apparent Calcium Binding Affinities: Insights from Parvalbumins.

Members of the parvalbumin (PV) family of calcium (Ca) binding proteins (CBPs) share a relatively high level of sequence similarity. However, their Ca affinities and selectivities against competing ions like Mg can widely vary. We conducted molecular dynamics simulations of several α-parvalbumin (αPV) constructs with micromolar to nanomolar Ca affinities to identify structural and dynamic features that contribute to their binding of ions.

Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium.

Troponin C (TnC) is a critical regulator of skeletal muscle contraction; it binds Ca2+ to activate muscle contraction. Surprisingly, the gene encoding fast skeletal TnC (TNNC2) has not yet been implicated in muscle disease. Here, we report 2 families with pathogenic variants in TNNC2.

Long QT Syndrome Type 2: Emerging Strategies for Correcting Class 2 () Mutations and Identifying New Patients.

Significant advances in our understanding of the molecular mechanisms that cause congenital long QT syndrome (LQTS) have been made. A wide variety of experimental approaches, including heterologous expression of mutant ion channel proteins and the use of inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LQTS patients offer insights into etiology and new therapeutic strategies. This review briefly discusses the major molecular mechanisms underlying LQTS type 2 (LQT2), which is caused by loss-of-function (LOF) mutations in the gene (also known as the human ether-à-go-go-related gene or ).

The Role of a Crystallographically Unresolved Cytoplasmic Loop in Stabilizing the Bacterial Membrane Insertase YidC2.

YidC, a bacterial member of the YidC/Alb3/Oxa1 insertase family, mediates membrane protein assembly and insertion. Cytoplasmic loops are known to have functional significance in membrane proteins such as YidC. Employing microsecond-level molecular dynamics (MD) simulations, we show that the crystallographically unresolved C2 loop plays a crucial role in the structural dynamics of Bacillus halodurans YidC2.

Lipid-Dependent Alternating Access Mechanism of a Bacterial Multidrug ABC Exporter.

By undergoing conformational changes, active membrane transporters alternate between an inward-facing (IF) and an outward-facing (OF) state to transport their substrates across cellular membrane. The conformational landscape of membrane transporters, however, could be influenced by their environment, and the dependence of the alternating access mechanism on the lipid composition has not been understood at the molecular level. We have performed an extensive set of microsecond-level all-atom molecular dynamics (MD) simulations on bacterial ATP binding cassette (ABC) exporter Sav1866 in six different phosphocholine (PC) and phosphoethanolamine (PE) lipid membrane environments.

What Can and Cannot Be Learned from Molecular Dynamics Simulations of Bacterial Proton-Coupled Oligopeptide Transporter GkPOT?

We have performed an extensive set of all-atom molecular dynamics (MD) simulations of a bacterial proton-coupled oligopeptide transporter (POT) in an explicit membrane environment. We have characterized both the local and global conformational dynamics of the transporter upon the proton and/or substrate binding, within a statistical framework. Our results reveal a clearly distinct behavior for local conformational dynamics in the absence and presence of the proton at the putative proton binding residue E310.

A review of monoamine transporter-ligand interactions.

Transporters of the monoamines serotonin, dopamine, and norepinephrine are plasma membrane proteins belonging to the neurotransmitter sodium symporter family (NSS). Monoamine transporters (MATs) by facilitating reuptake of neurotransmitters from the synapse into the presynaptic nerve terminal, regulate neurotransmitter chemical signaling and maintain homeostasis. MATs are targets for several psychostimulants such as cocaine and amphetamine; and also for drugs treating several psychiatric disorders such as depression, attention deficit hyperactivity disorder, Parkinson's disease, and schizophrenia.

New design strategies for antidepressant drugs.

Introduction: In spite of research efforts spanning six decades, the most prominent antidepressant drugs to date still carry several adverse effects, often serious enough to warrant discontinuation of the drug. Molecular mechanisms of depression are now better understood such that some of the specific receptors responsible can be targeted for activation or inhibition. This advance, coupled with the recent availability of crystal structures of relevant drug targets or their homologs, has opened the door for new antidepressant therapeutic compounds.