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Journal of Biochemistry Jun 1998The intracellular sorting of newly synthesized precursor proteins (preproteins) to mitochondria depends on the "mitochondria-targeting sequence" (MTS), which is located... (Review)
Review
The intracellular sorting of newly synthesized precursor proteins (preproteins) to mitochondria depends on the "mitochondria-targeting sequence" (MTS), which is located at the amino termini of the preproteins. MTS is required, however, not only for targeting newly synthesized preproteins to mitochondria, but also for all the following steps along the mitochondrial protein import pathway. MTS of nascent preproteins is first recognized by a cytoplasmic molecular chaperone, MSF, and then by Tom70 and Tom20 of the mitochondrial outer membrane receptor complex, Tom5 and Tom40 of the outer membrane protein translocation machinery, Tim23 of the inner membrane protein translocation machinery, and finally the processing peptidase, MPP, in the matrix. MTS is a multi-role sorting sequence which specifically interacts with various components along the mitochondrial protein import pathway. Recognition of MTS at multiple steps during the import of preproteins may contribute to the strict sorting of proteins destined for mitochondria.
Topics: 14-3-3 Proteins; Amino Acid Sequence; Animals; Biological Transport; Carrier Proteins; Fungal Proteins; Humans; Membrane Proteins; Membrane Transport Proteins; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Molecular Chaperones; Molecular Sequence Data; Proteins; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Saccharomyces cerevisiae Proteins; Sequence Analysis
PubMed: 9603986
DOI: 10.1093/oxfordjournals.jbchem.a022036 -
Blood Apr 2014TAM receptors (Tyro3, Axl, and Mer) belong to a family of receptor tyrosine kinases that have important effects on hemostasis and inflammation. Also, they affect cell... (Review)
Review
TAM receptors (Tyro3, Axl, and Mer) belong to a family of receptor tyrosine kinases that have important effects on hemostasis and inflammation. Also, they affect cell proliferation, survival, adhesion, and migration. TAM receptors can be activated by the vitamin K-dependent proteins Gas6 and protein S. Protein S is more commonly known as an important cofactor for protein C as well as a direct inhibitor of multiple coagulation factors. To our knowledge, the functions of Gas6 are limited to TAM receptor activation. When activated, the TAM receptors have effects on primary hemostasis and coagulation and display an anti-inflammatory or a proinflammatory effect, depending on cell type. To comprehend the effects that the TAM receptors and their ligands have on hemostasis and inflammation, we compare studies that report the different phenotypes displayed by mice with deficiencies in the genes of this receptor family and its ligands (protein S(+/-), Gas6(-/-), TAM(-/-), and variations of these). In this manner, we aim to display which features are attributable to the different ligands. Because of the effects TAM receptors have on hemostasis, inflammation, and cancer growth, their modulation could make interesting therapeutic targets in thromboembolic disease, atherosclerosis, sepsis, autoimmune disease, and cancer.
Topics: Animals; Hemostasis; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Mice; Protein S; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; c-Mer Tyrosine Kinase; Axl Receptor Tyrosine Kinase
PubMed: 24596417
DOI: 10.1182/blood-2013-09-528752 -
IUBMB Life 2001Most mitochondrial proteins are encoded by the nuclear genome and thus have to be imported into mitochondria from the cytosol. Protein translocation across and into the... (Review)
Review
Most mitochondrial proteins are encoded by the nuclear genome and thus have to be imported into mitochondria from the cytosol. Protein translocation across and into the mitochondrial membranes is a multistep process facilitated by the coordinated action of at least four specialized translocation systems in the outer and inner membranes of mitochondria. The outer membrane contains one general translocase, the TOM complex, whereas three distinct translocases are located in the inner membrane, which facilitates translocation of different classes of preproteins. The TIM23 complex mediates import of matrix-targeted preproteins with N-terminal presequences, whereas hydrophobic preproteins with internal targeting signals are inserted into the inner membrane via the TIM22 complex. The OXA translocase mediates the insertion of preproteins from the matrix space into the inner membrane. This review focuses on the structural organization and function of the import machinery of the model organisms of Saccharomyces cerevisiae and Neurospora crassa. In addition, the molecular basis of a new human mitochondrial disorder is discussed, the Mohr-Tranebjaerg syndrome. This is the first known disease, which is caused by an impaired mitochondrial protein import machinery leading to progressive neurodegeneration.
Topics: Animals; Carrier Proteins; Humans; Intracellular Membranes; Macromolecular Substances; Membrane Proteins; Membrane Transport Proteins; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; Protein Transport; Saccharomyces cerevisiae Proteins; Signal Transduction
PubMed: 11798021
DOI: 10.1080/15216540152845894 -
Annals of Laboratory Medicine Jan 2013Thrombophilia that is common among Caucasians is caused by genetic polymorphisms of coagulation factor V Leiden (R506Q) and prothrombin G20210A. Unlike that in... (Review)
Review
Thrombophilia that is common among Caucasians is caused by genetic polymorphisms of coagulation factor V Leiden (R506Q) and prothrombin G20210A. Unlike that in Caucasians, thrombophilia that is common in the Japanese and Chinese involve dysfunction of the activated protein C (APC) anticoagulant system caused by abnormal protein S and protein C molecules. Approximately 50% of Japanese and Chinese individuals who develop venous thrombosis have reduced activities of protein S. The abnormal sites causing the protein S molecule abnormalities are distributed throughout the protein S gene, PROS1. One of the most common abnormalities is protein S Tokushima (K155E), which accounts for about 30% of the protein S molecule abnormalities in the Japanese. Whether APC dysfunction occurs in other Asian countries is an important aspect of mapping thrombophilia among Asians. International surveys using an accurate assay system are needed to determine this.
Topics: Asian People; Blood Coagulation; Blood Proteins; Humans; Protein C; Protein S; Thrombophilia; Venous Thrombosis
PubMed: 23301217
DOI: 10.3343/alm.2013.33.1.8 -
BMC Genomics Sep 2018The protein energy landscape underscores the inherent nature of proteins as dynamic molecules interconverting between structures with varying energies. Reconstructing a...
BACKGROUND
The protein energy landscape underscores the inherent nature of proteins as dynamic molecules interconverting between structures with varying energies. Reconstructing a protein's energy landscape holds the key to characterizing a protein's equilibrium conformational dynamics and its relationship to function. Many pathogenic mutations in protein sequences alter the equilibrium dynamics that regulates molecular interactions and thus protein function. In principle, reconstructing energy landscapes of a protein's healthy and diseased variants is a central step to understanding how mutations impact dynamics, biological mechanisms, and function.
RESULTS
Recent computational advances are yielding detailed, sample-based representations of protein energy landscapes. In this paper, we propose and describe two novel methods that leverage computed, sample-based representations of landscapes to reconstruct them and extract from them informative local structures that reveal the underlying organization of an energy landscape. Such structures constitute landscape features that, as we demonstrate here, can be utilized to detect alterations of landscapes upon mutation.
CONCLUSIONS
The proposed methods detect altered protein energy landscape features in response to sequence mutations. By doing so, the methods allow formulating hypotheses on the impact of mutations on specific biological activities of a protein. This work demonstrates that the availability of energy landscapes of healthy and diseased variants of a protein opens up new avenues to harness the quantitative information embedded in landscapes to summarize mechanisms via which mutations alter protein dynamics to percolate to dysfunction.
Topics: Algorithms; Computational Biology; Humans; Models, Molecular; Mutation; Protein Conformation; Proteins; Thermodynamics
PubMed: 30255791
DOI: 10.1186/s12864-018-5024-z -
The FEBS Journal Dec 2006Gas6 and protein S are two homologous secreted proteins that depend on vitamin K for their execution of a range of biological functions. A discrete subset of these... (Review)
Review
Gas6 and protein S are two homologous secreted proteins that depend on vitamin K for their execution of a range of biological functions. A discrete subset of these functions is mediated through their binding to and activation of the receptor tyrosine kinases Axl, Sky and Mer. Furthermore, a hallmark of the Gas6-Axl system is the unique ability of Gas6 and protein S to tether their non receptor-binding regions to the negatively charged membranes of apoptotic cells. Numerous studies have shown the Gas6-Axl system to regulate cell survival, proliferation, migration, adhesion and phagocytosis. Consequently, altered activity/expression of its components has been detected in a variety of pathologies such as cancer and vascular, autoimmune and kidney disorders. Moreover, Axl overactivation can equally occur without ligand binding, which has implications for tumorigenesis. Further knowledge of this exquisite ligand-receptor system and the circumstances of its activation should provide the basis for development of novel therapies for the above diseases.
Topics: Animals; Apoptosis; Cell Adhesion; Crystallography, X-Ray; Humans; Intercellular Signaling Peptides and Proteins; Ligands; Models, Biological; Neoplasms; Oncogene Proteins; Protein S; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Saccharomyces cerevisiae Proteins; Signal Transduction; Vitamin K; c-Mer Tyrosine Kinase; Axl Receptor Tyrosine Kinase
PubMed: 17064312
DOI: 10.1111/j.1742-4658.2006.05529.x -
Journal of Thrombosis and Haemostasis :... Dec 2019Activated protein C (APC)-mediated inactivation of factor (F)Va is greatly enhanced by protein S. For inactivation to occur, a trimolecular complex among FVa, APC, and...
BACKGROUND
Activated protein C (APC)-mediated inactivation of factor (F)Va is greatly enhanced by protein S. For inactivation to occur, a trimolecular complex among FVa, APC, and protein S must form on the phospholipid membrane. However, direct demonstration of complex formation has proven elusive.
OBJECTIVES
To elucidate the nature of the phospholipid-dependent interactions among APC, protein S, and FVa.
METHODS
We evaluated binding of active site blocked APC to phospholipid-coated magnetic beads in the presence and absence of protein S and/or FVa. The importance of protein S and FV residues were evaluated functionally.
RESULTS
Activated protein C alone bound weakly to phospholipids. Protein S mildly enhanced APC binding to phospholipid surfaces, whereas FVa did not. However, FVa together with protein S enhanced APC binding (>14-fold), demonstrating formation of an APC/protein S/FVa complex. C4b binding protein-bound protein S failed to enhance APC binding, agreeing with its reduced APC cofactor function. Protein S variants (E36A and D95A) with reduced APC cofactor function exhibited essentially normal augmentation of APC binding to phospholipids, but diminished APC/protein S/FVa complex formation, suggesting involvement in interactions dependent upon FVa. Similarly, FVa (W1920R), an APC-resistant FV variant, also did not efficiently incorporate into the trimolecular complex as efficiently as wild-type FVa. FVa inactivation assays suggested that the mutation impairs its affinity for phospholipid membranes and with protein S within the complex.
CONCLUSIONS
FVa plays a central role in the formation of its inactivation complex. Furthermore, membrane proximal interactions among FVa, APC, and protein S are essential for its cofactor function.
Topics: Binding Sites; Blood Coagulation; Calcium-Binding Proteins; Enzyme Activation; Factor Va; HEK293 Cells; Humans; Models, Molecular; Multiprotein Complexes; Phospholipids; Protein Binding; Protein C; Protein Conformation; Protein S; Structure-Activity Relationship; Thrombin; Thromboplastin
PubMed: 31364267
DOI: 10.1111/jth.14594 -
Blood Aug 1994Regulation of C4b-binding protein (C4BP) isoforms during acute phase and its relationship to the plasma concentration of free protein S was elucidated. An assay for beta...
Regulation of C4b-binding protein (C4BP) isoforms during acute phase and its relationship to the plasma concentration of free protein S was elucidated. An assay for beta chain containing C4BP (C4BP beta+) was developed and the concentrations of total C4BP, C4BP beta+, total, free, and bound protein S were measured in patients with acute-phase response. Even though total C4BP was increased to 162% (mean value) of controls, the corresponding value of C4BP beta+ was only 122%. In the acute-phase group, total protein S was increased to the same extent as C4BP beta+ (mean value of 124%), whereas free protein S was not decreased. In controls, total and bound protein S correlated with total C4BP and C4BP beta+. However, in the acute-phase group, the correlation between bound protein S and total C4BP was lost, although the correlation between C4BP beta+ and protein S remained. The present results suggest stable levels of free protein S during acute phase to be the result of differential regulation of C4BP alpha- and beta-chain expression, and the concentration of free protein S to be the resulting molar excess of protein S over C4BP beta+. This mechanism ensures functional levels of free anticoagulant protein S despite high levels of C4BP.
Topics: Acute-Phase Proteins; Acute-Phase Reaction; Antibodies, Monoclonal; Calcium; Carrier Proteins; Complement C4b; Complement Inactivator Proteins; Glycoproteins; Humans; Macromolecular Substances; Protein S
PubMed: 7519078
DOI: No ID Found -
Biochimica Et Biophysica Acta 2009Sin3 was isolated over two decades ago as a negative regulator of transcription in budding yeast. Subsequent research has established the protein as a master... (Review)
Review
Sin3 was isolated over two decades ago as a negative regulator of transcription in budding yeast. Subsequent research has established the protein as a master transcriptional scaffold and corepressor capable of transcriptional silencing via associated histone deacetylases (HDACs). The core Sin3-HDAC complex interacts with a wide variety of repressors and corepressors, providing flexibility and expanded specificity in modulating chromatin structure and transcription. As a result, the Sin3/HDAC complex is involved in an array of biological and cellular processes, including cell cycle progression, genomic stability, embryonic development, and homeostasis. Abnormal recruitment of this complex or alteration of its enzymatic activity has been implicated in neoplastic transformation.
Topics: Autophagy-Related Proteins; Carrier Proteins; Genes, Fungal; Histone Deacetylase 2; Histone Deacetylases; Multiprotein Complexes; Protein Structure, Tertiary; RNA-Binding Proteins; Repressor Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 19505602
DOI: 10.1016/j.bbagrm.2009.05.007 -
Molecular Biology of the Cell Aug 2012Acute stress causes a rapid redistribution of protein quality control components and aggregation-prone proteins to diverse subcellular compartments. How these remarkable...
Acute stress causes a rapid redistribution of protein quality control components and aggregation-prone proteins to diverse subcellular compartments. How these remarkable changes come about is not well understood. Using a phenotypic reporter for a synthetic yeast prion, we identified two protein-sorting factors of the Hook family, termed Btn2 and Cur1, as key regulators of spatial protein quality control in Saccharomyces cerevisiae. Btn2 and Cur1 are undetectable under normal growth conditions but accumulate in stressed cells due to increased gene expression and reduced proteasomal turnover. Newly synthesized Btn2 can associate with the small heat shock protein Hsp42 to promote the sorting of misfolded proteins to a peripheral protein deposition site. Alternatively, Btn2 can bind to the chaperone Sis1 to facilitate the targeting of misfolded proteins to a juxtanuclear compartment. Protein redistribution by Btn2 is accompanied by a gradual depletion of Sis1 from the cytosol, which is mediated by the sorting factor Cur1. On the basis of these findings, we propose a dynamic model that explains the subcellular distribution of misfolded proteins as a function of the cytosolic concentrations of molecular chaperones and protein-sorting factors. Our model suggests that protein aggregation is not a haphazard process but rather an orchestrated cellular response that adjusts the flux of misfolded proteins to the capacities of the protein quality control system.
Topics: Amino Acid Transport Systems; Cell Nucleus; Gene Knockout Techniques; Green Fluorescent Proteins; HSP40 Heat-Shock Proteins; Heat-Shock Proteins; Heat-Shock Response; Karyopherins; Microscopy, Fluorescence; Molecular Chaperones; Nuclear Localization Signals; Phenotype; Prions; Protein Binding; Protein Multimerization; Protein Transport; Recombinant Fusion Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 22718905
DOI: 10.1091/mbc.E12-03-0194