scholarly journals Transmembrane signaling and cytoplasmic signal conversion by dimeric transmembrane helix 2 and a linker domain of the DcuS sensor kinase

2020 ◽  
pp. jbc.RA120.015999
Author(s):  
Marius Stopp ◽  
Philipp Aloysius Steinmetz ◽  
Christopher Schubert ◽  
Christian Griesinger ◽  
Dirk Schneider ◽  
...  
Keyword(s):  
Signal Transmission ◽  
Transmembrane Helix ◽  
Helical Structure ◽  
Kinase Domain ◽  
Sensor Kinase ◽  
Transmembrane Signaling ◽  
Activated State ◽  
Sensor Kinases ◽  
And Function ◽  
Cytoplasmic Side

Transmembrane signaling is a key process of membrane bound sensor kinases. The C4-dicarboxylate (fumarate) responsive sensor kinase DcuS of Escherichia coli is anchored by transmembrane helices TM1 and TM2 in the membrane. Signal transmission across the membrane relies on the piston-type movement of the periplasmic part of TM2. To define the role of TM2 in transmembrane signaling, we use oxidative Cys cross-linking to demonstrate that TM2 extends over the full distance of the membrane and forms a stable transmembrane homodimer in both the inactive and fumarate-activated state of DcuS. A S186xxxGxxxG194 motif is required for the stability and function of the TM2 homodimer. The TM2 helix further extends on the periplasmic side into the α6-helix of the sensory PASP domain, and on the cytoplasmic side into the α1-helix of PASC. PASC has to transmit the signal to the C-terminal kinase domain. A helical linker on the cytoplasmic side connecting TM2 with PASC contains a LxxxLxxxL sequence. The dimeric state of the linker was relieved during fumarate activation of DcuS, indicating structural rearrangements in the linker. Thus, DcuS contains a long α-helical structure reaching from the sensory PASP (α6) domain across the membrane to α1(PASC). Taken together, the results suggest piston-type transmembrane signaling by the TM2-homodimer from PASP across the full TM region, whereas the fumarate-destabilized linker dimer converts the signal on the cytoplasmic side for PASC and kinase regulation.

scholarly journals The role of prolines and glycine in the transmembrane domain of LAT

2020 ◽  
Author(s):  
Daniela Glatzová ◽  
Harsha Mavila ◽  
Maria Chiara Saija ◽  
Tomáš Chum ◽  
Lukasz Cwiklik ◽  
...  
Keyword(s):  
Amino Acids ◽  
Plasma Membrane ◽  
Transmembrane Domain ◽  
Transmembrane Helix ◽  
Helical Structure ◽  
Surface Expression ◽  
Transmembrane Segment ◽  
Proline Residue ◽  
And Function ◽  
The Impact

ABSTRACTLAT is a critical regulator of T cell development and function. It organises signalling events at the plasma membrane. However, the mechanism, which controls LAT localisation at the plasma membrane is not fully understood. Here, we studied the impact of helix-breaking amino acids, two prolines and one glycine, in the transmembrane segment on localisation and function of LAT. Using in silico analysis, confocal and superresolution imaging and flow cytometry we demonstrate that central proline residue destabilises transmembrane helix by inducing a kink. The helical structure and dynamics is further regulated by glycine and another proline residue in the luminal part of LAT transmembrane domain. Replacement of these residues with aliphatic amino acids reduces LAT dependence on palmitoylation for sorting to the plasma membrane. However, surface expression of these mutants is not sufficient to recover function of non-palmitoylated LAT in stimulated T cells. These data indicate that geometry and dynamics of LAT transmembrane segment regulate its localisation and function in immune cells.

scholarly journals Secondary structure and biophysical activity of synthetic analogues of the pulmonary surfactant polypeptide SP-C

1995 ◽  
Vol 307 (2) ◽  
pp. 535-541 ◽  
Author(s):  
J Johansson ◽  
G Nilsson ◽  
R Strömberg ◽  
B Robertson ◽  
H Jörnvall ◽  
...  
Keyword(s):  
Secondary Structure ◽  
Pulmonary Surfactant ◽  
Transmembrane Helix ◽  
Helical Structure ◽  
Helical Conformation ◽  
Synthetic Analogues ◽  
Charged Amino Acids ◽  
Phospholipid Micelles ◽  
Helical Content ◽  
Biophysical Activity

Native pulmonary-surfactant-associated lipopolypeptide SP-C, its chemically depalmitoylated form and several synthetic analogues lacking the palmitoylcysteine residues were analysed for secondary structure in phospholipid micelles and for biophysical activity in 1,2-dipalmitoyl-sn-glycero-3- phosphocholine/phosphatidylglycerol/palmitic acid (68:22:9, by wt.). Compared with the native molecule, with the entire poly-valyl part in a known alpha-helical conformation, depalmitoylated SP-C was found to be still mainly alpha-helical, but with an approx. 20% decrease in the helical content. A synthetic hybrid polypeptide where the entire poly-valyl alpha-helical part of native SP-C had been replaced with the amino acid sequence of a transmembrane helix of bacteriorhodopsin is also predominantly alpha-helical. In contrast, synthetic SP-C analogues lacking only the palmitoyl groups, by replacement of the palmitoylcysteine residues with cysteine, phenylalanine or serine, or lacking the positively charged amino acids by replacement with alanine, are considerably less alpha-helical than both native and depalmitoylated SP-C. The data indicate that the SP-C palmitoyl groups are important for maintenance of the alpha-helical conformation in parts of the polypeptide, and that the poly-valyl alpha-helical conformation is not fully formed in synthetic SP-C polypeptides. Furthermore, the helical structure of both native and depalmitoylated SP-C in dodecylphosphocholine micelles is very resistant to thermal denaturation, exhibiting ordered structure at 90 degrees C. The alpha-helical content grossly parallels the peptide-induced acceleration of the spreading of phospholipids at an air/water interface and the increase of surface pressure. The data suggest that the alpha-helical conformation itself, rather than just the covalent structure, is of prime importance for the biological function of synthetic pulmonary-surfactant peptides.

scholarly journals Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1690
Author(s):  
Louise Pinet ◽  
Nadine Assrir ◽  
Carine van Heijenoort
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Domain ◽  
Cellular Motility ◽  
Dynamic Features ◽  
Sh2 Domains ◽  
Intrinsically Disordered ◽  
Src Homology ◽  
Regulation Functions ◽  
And Function

ErbBs are receptor tyrosine kinases involved not only in development, but also in a wide variety of diseases, particularly cancer. Their extracellular, transmembrane, juxtamembrane, and kinase folded domains were described extensively over the past 20 years, structurally and functionally. However, their whole C-terminal tails (CTs) following the kinase domain were only described at atomic resolution in the last 4 years. They were shown to be intrinsically disordered. The CTs are known to be tyrosine-phosphorylated when the activated homo- or hetero-dimers of ErbBs are formed. Their phosphorylation triggers interaction with phosphotyrosine binding (PTB) or Src Homology 2 (SH2) domains and activates several signaling pathways controling cellular motility, proliferation, adhesion, and apoptosis. Beyond this passive role of phosphorylated domain and site display for partners, recent structural and function studies unveiled active roles in regulation of phosphorylation and interaction: the CT regulates activity of the kinase domain; different phosphorylation states have different compaction levels, potentially modulating the succession of phosphorylation events; and prolines have an important role in structure, dynamics, and possibly regulatory interactions. Here, we review both the canonical role of the disordered CT domains of ErbBs as phosphotyrosine display domains and the recent findings that expand the known range of their regulation functions linked to specific structural and dynamic features.

scholarly journals Form and Function Predict Acoustic Transmission Properties of the Songs of Male and Female Canyon Wrens

2021 ◽  
Vol 9 ◽  
Author(s):  
Lauryn Benedict ◽  
Braelei Hardt ◽  
Lorraine Dargis
Keyword(s):  
Signal Transmission ◽  
Male And Female ◽  
Male Song ◽  
Form And Function ◽  
Transmission Properties ◽  
Use Context ◽  
Males And Females ◽  
Song Transmission ◽  
Typical Habitat ◽  
And Function

To function effectively, animal signals must transmit through the environment to receivers, and signal transmission properties depend on signal form. Here we investigated how the transmission of multiple parts of a well-studied signal, bird song, varies between males and females of one species. We hypothesized that male and female songs would have different transmission properties, reflecting known differences in song form and function. We further hypothesized that two parts of male song used differentially in broadcast singing and aggressive contests would transmit differently. Analyses included male and female songs from 20 pairs of canyon wrens (Catherpes mexicanus) played and re-recorded in species-typical habitat. We found that male song cascades used in broadcast singing propagated farther than female songs, with higher signal-to-noise ratios at distance. In contrast, we demonstrated relatively restricted propagation of the two vocalization types typically used in short-distance aggressive signaling, female songs and male “cheet” notes. Of the three tested signals, male “cheet” notes had the shortest modeled propagation distances. Male and female signals blurred similarly, with variable patterns of excess attenuation. Both male song parts showed more consistent transmission across the duration of the signal than did female songs. Song transmission, thus, varied by sex and reflected signal form and use context. Results support the idea that males and females of the same species can show distinctly different signal evolution trajectories. Sexual and social selection pressures can shape sex-specific signal transmission, even when males and females are communicating in shared physical environments.

scholarly journals Mechanical Chirality of Rotaxanes: Synthesis and Function

Symmetry ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 144 ◽  
Author(s):  
Kazuko Nakazono ◽  
Toshikazu Takata
Keyword(s):  
Helical Structure ◽  
Chiral Molecules ◽  
Polymer Systems ◽  
Property Change ◽  
Recent Advances ◽  
Potential Applicability ◽  
And Function

Mechanically chiral molecules have attracted considerable attention due to their property and function based on its unique interlocked structure. This review covers the recent advances in the synthesis and function of interlocked rotaxanes with mechanical chirality along with their dynamic and complex stereochemistry. The application of mechanically chiral rotaxanes to control the polymer helical structure is also introduced, where amplification of mechanical chirality appears to cause the macroscopic polymer property change, suggesting the potential applicability of mechanical chirality in polymer systems.

scholarly journals Influence of Transmembrane Helix Mutations on Cytochrome P450-Membrane Interactions and Function

2019 ◽  
Vol 116 (3) ◽  
pp. 419-432 ◽  
Author(s):  
Ghulam Mustafa ◽  
Prajwal P. Nandekar ◽  
Tyler J. Camp ◽  
Neil J. Bruce ◽  
Michael C. Gregory ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Transmembrane Helix ◽  
Membrane Interactions ◽  
And Function

scholarly journals Characterization of the PAS domain in the sensor-kinase BvgS: mechanical role in signal transmission

2013 ◽  
Vol 13 (1) ◽  
pp. 172 ◽  
Author(s):  
Elian Dupré ◽  
Alexandre Wohlkonig ◽  
Julien Herrou ◽  
Camille Locht ◽  
Françoise Jacob-Dubuisson ◽  
...  
Keyword(s):  
Signal Transmission ◽  
Sensor Kinase ◽  
Pas Domain

scholarly journals Tyr198 is the Essential Autophosphorylation Site for STK16 Localization and Kinase Activity

2019 ◽  
Vol 20 (19) ◽  
pp. 4852 ◽  
Author(s):  
Junjun Wang ◽  
Juanjuan Liu ◽  
Xinmiao Ji ◽  
Xin Zhang
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Kinase Domain ◽  
Serine Threonine Kinase ◽  
Cycle Progression ◽  
Threonine Kinase ◽  
Cellular Processes ◽  
Activation Segment ◽  
And Function

STK16, reported as a Golgi localized serine/threonine kinase, has been shown to participate in multiple cellular processes, including the TGF-β signaling pathway, TGN protein secretion and sorting, as well as cell cycle and Golgi assembly regulation. However, the mechanisms of the regulation of its kinase activity remain underexplored. It was known that STK16 is autophosphorylated at Thr185, Ser197, and Tyr198 of the activation segment in its kinase domain. We found that STK16 localizes to the cell membrane and the Golgi throughout the cell cycle, but mutations in the auto-phosphorylation sites not only alter its subcellular localization but also affect its kinase activity. In particular, the Tyr198 mutation alone significantly reduced the kinase activity of STK16, abolished its Golgi and membrane localization, and affected the cell cycle progression. This study demonstrates that a single site autophosphorylation of STK16 could affect its localization and function, which provides insights into the molecular regulatory mechanism of STK16’s kinase activity.

scholarly journals The dynamic switch mechanism that leads to activation of LRRK2 is embedded in the DFGψ motif in the kinase domain

2019 ◽  
Vol 116 (30) ◽  
pp. 14979-14988 ◽  
Author(s):  
Sven H. Schmidt ◽  
Matthias J. Knape ◽  
Daniela Boassa ◽  
Natascha Mumdey ◽  
Alexandr P. Kornev ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Regulatory Mechanism ◽  
Kinase Domain ◽  
Leucine Rich Repeat ◽  
Wild Type ◽  
Conformational Switch ◽  
Multidomain Protein ◽  
Switch Mechanism ◽  
And Function

Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain protein, and LRRK2 mutants are recognized risk factors for Parkinson’s disease (PD). Although the precise mechanisms that control LRRK2 regulation and function are unclear, the importance of the kinase domain is strongly implicated, since 2 of the 5 most common familial LRRK2 mutations (G2019S and I2020T) are localized to the conserved DFGψ motif in the kinase core, and kinase inhibitors are under development. Combining the concept of regulatory (R) and catalytic (C) spines with kinetic and cell-based assays, we discovered a major regulatory mechanism embedded within the kinase domain and show that the DFG motif serves as a conformational switch that drives LRRK2 activation. LRRK2 is quite unusual in that the highly conserved Phe in the DFGψ motif, which is 1 of the 4 R-spine residues, is replaced with tyrosine (DY2018GI). A Y2018F mutation creates a hyperactive phenotype similar to the familial mutation G2019S. The hydroxyl moiety of Y2018 thus serves as a “brake” that stabilizes an inactive conformation; simply removing it destroys a key hydrogen-bonding node. Y2018F, like the pathogenic mutant I2020T, spontaneously forms LRRK2-decorated microtubules in cells, while the wild type and G2019S require kinase inhibitors to form filaments. We also explored 3 different mechanisms that create kinase-dead pseudokinases, including D2017A, which further emphasizes the highly synergistic role of key hydrophobic and hydrophilic/charged residues in the assembly of active LRRK2. We thus hypothesize that LRRK2 harbors a classical protein kinase switch mechanism that drives the dynamic activation of full-length LRRK2.

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