RESUMEN
The sarco-endoplasmic reticulum calcium ATPase (SERCA) is responsible for maintaining calcium homeostasis in all eukaryotic cells by actively transporting calcium from the cytosol into the sarco-endoplasmic reticulum (SR/ER) lumen. Calcium is an important signaling ion, and the activity of SERCA is critical for a variety of cellular processes such as muscle contraction, neuronal activity, and energy metabolism. SERCA is regulated by several small transmembrane peptide subunits that are collectively known as the "regulins". Phospholamban (PLN) and sarcolipin (SLN) are the original and most extensively studied members of the regulin family. PLN and SLN inhibit the calcium transport properties of SERCA and they are required for the proper functioning of cardiac and skeletal muscles, respectively. Myoregulin (MLN), dwarf open reading frame (DWORF), endoregulin (ELN), and another-regulin (ALN) are newly discovered tissue-specific regulators of SERCA. Herein, we compare the functional properties of the regulin family of SERCA transmembrane peptide subunits and consider their regulatory mechanisms in the context of the physiological and pathophysiological roles of these peptides. We present new functional data for human MLN, ELN, and ALN, demonstrating that they are inhibitors of SERCA with distinct functional consequences. Molecular modeling and molecular dynamics simulations of SERCA in complex with the transmembrane domains of MLN and ALN provide insights into how differential binding to the so-called inhibitory groove of SERCA-formed by transmembrane helices M2, M6, and M9-can result in distinct functional outcomes.
Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Calcio/metabolismo , Proteínas Musculares/metabolismo , Proteolípidos/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Animales , Proteínas de Unión al Calcio/genética , Humanos , Modelos Moleculares , Proteínas Musculares/genética , Proteolípidos/genética , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genéticaRESUMEN
BACKGROUND: Papillomavirus binding factor (PBF) or zinc finger protein 395 is a transcription factor associated to a poor prognosis in patients with osteosarcoma, an aggressive bone cancer that predominantly affects adolescents. To investigate the role of the PBF protein in the osteosarcoma genesis, in this paper we present the bioinformatics analysis of physicochemical properties of PBF and its probable interactions with several key cellular targets. RESULTS: The physicochemical characteristics determined to PBF, disorder-promoting amino acids, flexibility, hydrophobicity, prediction of secondary and tertiary structures and probability to be crystallized, supported that this protein can be considered as an intrinsically disordered protein (IDP), with a zinc finger-like domain. The in silico analysis to find out PBF interactions with cellular factors, confirmed the experimentally demonstrated interaction of PBF with two key cellular proteins involved in regulation of cellular apoptosis, 14-3-3ß and Scythe/BAT3 proteins. Furthermore, other interactions were found with proteins like HDAC1 and TPR which are known to be deregulated in several cancers. Experimental confirmation of specific interactions will contribute to understand the osteosarcoma process and might lead to the identification of new targets for diagnosis and treatments. CONCLUSIONS: According to the in silico PBF analyses, this protein can be considered as an IDP capable to bind several key cellular factors, and these interactions might play an important role in the osteosarcoma process.