Thymosin α1 Interacts with Exposed Phosphatidylserine in Membrane Models and in Cells and Uses Serum Albumin as a Carrier

Mandaliti, Walter; Nepravishta, Ridvan; Vallebona, P Sinibaldi; Pica, Francesca; Garaci, Enrico; Paci, Maurizio

doi:10.1021/acs.biochem.5b01345

Cited by 20 publications

(14 citation statements)

References 82 publications

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“…Thus, biological membranes have the potential to regulate ligand potency and efficacy, making the membrane a factor of particular relevance for ligand-receptor interactions. In support of this, numerous peptide hormones, including apelin and apela, have demonstrated binding to membrane-mimetics such as micelles and bicelles, leading to structural changes within the peptide 16 – 21 (reviewed, e.g., by Langelaan and Rainey 22 ).…”

Section: Introductionmentioning

confidence: 94%

Apelin conformational and binding equilibria upon micelle interaction primarily depend on membrane-mimetic headgroup

Shin

Sarker

Huang

et al. 2017

Sci Rep

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Apelin is one of two peptide hormones that activate the apelin receptor (AR or APJ) to regulate the cardiovascular system, central nervous system, and adipoinsular axis. Here, we apply circular dichroism (CD) spectropolarimetry and nuclear magnetic resonance (NMR) spectroscopy to characterize the potential membrane binding by the two longest bioactive apelin isoforms, apelin-55 and -36, using membrane-mimetic dodecylphosphocholine (DPC), sodium dodecyl sulfate (SDS), and 1-palmitoyl-2-hydroxy-sn-glycero-3-[phospho-rac-(1-glycerol)] (LPPG) micelles. Pulsed field gradient diffusion NMR experiments demonstrated preferential interaction of both apelin-55 and -36 with anionic SDS and LPPG micelles over zwitterionic DPC micelles. Chemical shift perturbations and changes in ps-ns scale dynamics of apelin-55 in all micelles were similarly localized along the polypeptide backbone, demonstrating clear dependence upon detergent headgroup, while comparison of chemical shifts between apelin-55 and apelin-36 showed negligible differences indicative of highly similar modes of micelle interaction. Notably, the observed behaviour was consistent with an ensemble averaged pair of free and bound states in fast exchange on the NMR timescale proportional to the fraction of micelle-bound protein, implying a similar conformational equilibrium regardless of headgroup and tailgroup. Membrane catalysis of apelin-AR binding would thus give rise to analogous behaviour in the essential C-terminal region common to all apelin isoforms.

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Section: Introductionmentioning

confidence: 94%

Apelin conformational and binding equilibria upon micelle interaction primarily depend on membrane-mimetic headgroup

Shin

Sarker

Huang

et al. 2017

Sci Rep

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“…After the complete assignments obtained on the basis of previous work on Tα1 [ 25 , 26 , 27 , 28 , 29 , 30 ] the preliminary analysis of the 15 N chemical shift by the algorithm of Wishart and Sykes corrected for short peptides [ 57 ] confirmed values characteristic of the presence of a short tract in helical conformation from residue Ser1 to Val5 in presence HA at 0.4% ( w / w ) concentration ( Figure 3 c).…”

Section: Resultsmentioning

confidence: 78%

“…The individual and sequential assignments of Tα1 were obtained by TOCSY and NOESY experiments with different mixing times as reported in the Materials and Methods. Heteronuclear 2D NMR spectra ( 15 N-HSQC) at natural abundance ( Figure 3 a) were used to overcome ambiguities and complete the assignments of the homonuclear 2D NMR spectra using the previously reported results [ 27 , 28 , 29 , 30 ]. The appearance of NOEs in the NH–NH region of the NOESY spectra reported in Figure 3 b allowed us to carry out the sequential assignment of the peptide; intense NH–NH (i, i + 1) NOEs strongly suggest the presence of a helical conformation [ 56 ].…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies with model membranes indicate that Tα1, unstructured in water solution, assumes tracts of helical conformation in structuring solvents like trifluoroethanol [ 25 , 26 ]. Interestingly, it assumes a conformation with two helical domains and inserts the first 5 residues of the N -terminal helix [ 27 , 28 , 29 , 30 ] in negative membranes models and particularly upon the phosphatidylserine (PS) exposure as found in several pathologies and apoptosis [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

“…These findings are in agreement with a growing body of evidence attesting the pleiotropy of this hormone peptide, which targets both normal and tumor cells interacting with multiple cellular components [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]; as such, they have generated a renewed interest. Studies of the serum Tα1 levels and of its interaction with soluble proteins [ 23 , 29 ] have also raised questions about the transport and localization of Tα1 in tissues and of the dynamics underlying the biological effects of this peptide in different clinical situations. All this research would benefit from a greater understanding of the Tα1 conformation and of the mechanism(s) involved in the interactions with other components of cells.…”

Section: Introductionmentioning

confidence: 99%

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Thymosin α1 Interacts with Hyaluronic Acid Electrostatically by Its Terminal Sequence LKEKK

et al. 2017

Self Cite

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Thymosin α1 (Tα1), is a peptidic hormone, whose immune regulatory properties have been demonstrated both in vitro and in vivo and approved in different countries for treatment of several viral infections and cancers. Tα1 assumes a conformation in negative membranes upon insertion into the phosphatidylserine exposure as found in several pathologies and in apoptosis. These findings are in agreement with the pleiotropy of Tα1, which targets both normal and tumor cells, interacting with multiple cellular components, and have generated renewed interest in the topic. Hyaluronan (HA) occurs ubiquitously in the extracellular matrix and on cell surfaces and has been related to a variety of diseases, and developmental and physiological processes. Proteins binding HA, among them CD44 and the Receptor for HA-mediated motility (RHAMM) receptors, mediate its biological effects. NMR spectroscopy indicated preliminarily that an interaction of Tα1 with HA occurs specifically around lysine residues of the sequence LKEKK of Tα1 and is suggestive of a possible interference of Tα1 in the binding of HA with CD44 and RHAMM. Further studies are needed to deepen these observations because Tα1 is known to potentiate the T-cell immunity and anti-tumor effect. The binding inhibitory activity of Tα1 on HA-CD44 or HA-RHAMM interactions can suppress both T-cell reactivity and tumor progression.

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Apelinergic System Structure and Function

Shin

Kenward

Rainey

2017

Comprehensive Physiology

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Apelin and apela (ELABELA/ELA/Toddler) are two peptide ligands for a class A G-protein-coupled receptor named the apelin receptor (AR/APJ/APLNR). Ligand-AR interactions have been implicated in regulation of the adipoinsular axis, cardiovascular system, and central nervous system alongside pathological processes. Each ligand may be processed into a variety of bioactive isoforms endogenously, with apelin ranging from 13 to 55 amino acids and apela from 11 to 32, typically being cleaved C-terminal to dibasic proprotein convertase cleavage sites. The C-terminal region of the respective precursor protein is retained and is responsible for receptor binding and subsequent activation. Interestingly, both apelin and apela exhibit isoform-dependent variability in potency and efficacy under various physiological and pathological conditions, but most studies focus on a single isoform. Biophysical behavior and structural properties of apelin and apela isoforms show strong correlations with functional studies, with key motifs now well determined for apelin. Unlike its ligands, the AR has been relatively difficult to characterize by biophysical techniques, with most characterization to date being focused on effects of mutagenesis. This situation may improve following a recently reported AR crystal structure, but there are still barriers to overcome in terms of comprehensive biophysical study. In this review, we summarize the three components of the apelinergic system in terms of structure-function correlation, with a particular focus on isoform-dependent properties, underlining the potential for regulation of the system through multiple endogenous ligands and isoforms, isoform-dependent pharmacological properties, and biological membrane-mediated receptor interaction. © 2018 American Physiological Society. Compr Physiol 8:407-450, 2018.

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Thymosin α1 Interacts with Exposed Phosphatidylserine in Membrane Models and in Cells and Uses Serum Albumin as a Carrier

Cited by 20 publications

References 82 publications

Apelin conformational and binding equilibria upon micelle interaction primarily depend on membrane-mimetic headgroup

Apelin conformational and binding equilibria upon micelle interaction primarily depend on membrane-mimetic headgroup

Thymosin α1 Interacts with Hyaluronic Acid Electrostatically by Its Terminal Sequence LKEKK

Apelinergic System Structure and Function

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