Biochimica et Biophysica Acta (BBA) - Biomembranes, 2013
The human immunodeficiency virus type 1 (HIV-1) p6 protein has recently been recognized as a dock... more The human immunodeficiency virus type 1 (HIV-1) p6 protein has recently been recognized as a docking site for several cellular and viral binding partners and is important for the formation of infectious viruses. Most of its known functions are suggested to occur under hydrophobic conditions near the cytoplasmic membrane, where the protein is presumed to exist in its most structured state. Although p6 is involved in manifold specific interactions, the protein has previously been considered to possess a random structure in aqueous solution. We show that p6 exhibits a defined structure with N- and C-terminal helical domains, connected by a flexible hinge region in 100mM dodecylphosphocholine micelle solution at pH 7 devoid of any organic co-solvents, indicating that this is a genuine limiting structural feature of the molecule in a hydrophobic environment. Furthermore, we show that p6 directly interacts with a cytoplasmic model membrane through both N-terminal and C-terminal regions by use of surface plasmon resonance (SPR) spectroscopy. Phosphorylation of Ser-40 located in the center of the C-terminal α-helix does not alter the secondary structure of the protein but amplifies the interaction with membranes significantly, indicating that p6 binds to the polar head groups at the surface of the cytoplasmic membrane. The increased hydrophobic membrane interaction of p6(23-52) S40F correlated with the observed increased amount of the polyprotein Gag in the RIPA insoluble fraction when Ser40 of p6 was mutated with Phe indicating that p6 modulates the membrane interactions of HIV-1 Gag.
Primary Sjögren&a... more Primary Sjögren's syndrome (pSS) is an autoimmune rheumatic disease mainly characterised by focal mononuclear cell infiltration in the salivary and lacrimal glands, and by the symptoms xerostomia and keratoconjunctivitis sicca. Germinal centre-like structures (GC) are found in the minor salivary glands of approximately 25% of patients. In this study, we aimed to assess genetic variations in pSS patients with GC-like formations (GC+) compared with patients without such formations (GC-). Minor salivary gland biopsies from Swedish and Norwegian pSS patients (n=320) were evaluated for GC-like formations, identifying 76 GC+ and 244 GC- patients. A panel of 1536 single-nucleotide polymorphisms (SNPs) in 107 genes was genotyped. Minor allele frequencies in GC+ and GC- patients were compared using Fisher's exact test, and associations were considered significant when p<4.7×10(-4) and suggestive when p<0.01. In this case-only analysis, we identified two SNPs in CCL11 (eotaxin) associated with GC-like structures (p<4.7×10(-4), OR 0.45 and 0.41, respectively). A haplotype of the two minor alleles was associated with GC status with p=2.6×10(-4), OR 0.40. Suggestive associations (p<0.01) were found in SNPs in the B cell activation and/or GC-formation related genes AICDA, BANK1 and BCL2. Furthermore, SNPs in IL17A, ICA1, PKN1 and SNPs in the NF-κB pathway genes CARD8, IKBKE and TANK were found suggestively associated with GC-like structures. Our findings suggest that genetic variations may explain why ectopic GC-like structures are present in some pSS patients, and support the hypothesis that GC+ and GC- patients represent distinct disease phenotypes.
Oral and maxillofacial surgery clinics of North America, 2014
Primary Sjögren's syndrome (pSS) is an autoimmune chronic inflammatory disorder affecting 0.2... more Primary Sjögren's syndrome (pSS) is an autoimmune chronic inflammatory disorder affecting 0.2% to 3.0% of the population, with a 9:1 female to male ratio. Features are oral and ocular dryness, local and systemic autoantibody production, and progressive focal mononuclear cell infiltration in the affected salivary and lacrimal glands. Lymphoma is the most severe complication of pSS, occurring in 4% to 5% of patients. Genetic studies identified an association with HLA and susceptibility genes in cytokine genes and genes involved in B-cell differentiation. Genetic variations may help explain why disease manifestations differ among patients and supports the hypothesis of certain distinct disease phenotypes.
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2013
The human immunodeficiency virus type 1 (HIV-1) p6 protein has recently been recognized as a dock... more The human immunodeficiency virus type 1 (HIV-1) p6 protein has recently been recognized as a docking site for several cellular and viral binding partners and is important for the formation of infectious viruses. Most of its known functions are suggested to occur under hydrophobic conditions near the cytoplasmic membrane, where the protein is presumed to exist in its most structured state. Although p6 is involved in manifold specific interactions, the protein has previously been considered to possess a random structure in aqueous solution. We show that p6 exhibits a defined structure with N- and C-terminal helical domains, connected by a flexible hinge region in 100mM dodecylphosphocholine micelle solution at pH 7 devoid of any organic co-solvents, indicating that this is a genuine limiting structural feature of the molecule in a hydrophobic environment. Furthermore, we show that p6 directly interacts with a cytoplasmic model membrane through both N-terminal and C-terminal regions by use of surface plasmon resonance (SPR) spectroscopy. Phosphorylation of Ser-40 located in the center of the C-terminal α-helix does not alter the secondary structure of the protein but amplifies the interaction with membranes significantly, indicating that p6 binds to the polar head groups at the surface of the cytoplasmic membrane. The increased hydrophobic membrane interaction of p6(23-52) S40F correlated with the observed increased amount of the polyprotein Gag in the RIPA insoluble fraction when Ser40 of p6 was mutated with Phe indicating that p6 modulates the membrane interactions of HIV-1 Gag.
Primary Sjögren&a... more Primary Sjögren's syndrome (pSS) is an autoimmune rheumatic disease mainly characterised by focal mononuclear cell infiltration in the salivary and lacrimal glands, and by the symptoms xerostomia and keratoconjunctivitis sicca. Germinal centre-like structures (GC) are found in the minor salivary glands of approximately 25% of patients. In this study, we aimed to assess genetic variations in pSS patients with GC-like formations (GC+) compared with patients without such formations (GC-). Minor salivary gland biopsies from Swedish and Norwegian pSS patients (n=320) were evaluated for GC-like formations, identifying 76 GC+ and 244 GC- patients. A panel of 1536 single-nucleotide polymorphisms (SNPs) in 107 genes was genotyped. Minor allele frequencies in GC+ and GC- patients were compared using Fisher's exact test, and associations were considered significant when p<4.7×10(-4) and suggestive when p<0.01. In this case-only analysis, we identified two SNPs in CCL11 (eotaxin) associated with GC-like structures (p<4.7×10(-4), OR 0.45 and 0.41, respectively). A haplotype of the two minor alleles was associated with GC status with p=2.6×10(-4), OR 0.40. Suggestive associations (p<0.01) were found in SNPs in the B cell activation and/or GC-formation related genes AICDA, BANK1 and BCL2. Furthermore, SNPs in IL17A, ICA1, PKN1 and SNPs in the NF-κB pathway genes CARD8, IKBKE and TANK were found suggestively associated with GC-like structures. Our findings suggest that genetic variations may explain why ectopic GC-like structures are present in some pSS patients, and support the hypothesis that GC+ and GC- patients represent distinct disease phenotypes.
Oral and maxillofacial surgery clinics of North America, 2014
Primary Sjögren's syndrome (pSS) is an autoimmune chronic inflammatory disorder affecting 0.2... more Primary Sjögren's syndrome (pSS) is an autoimmune chronic inflammatory disorder affecting 0.2% to 3.0% of the population, with a 9:1 female to male ratio. Features are oral and ocular dryness, local and systemic autoantibody production, and progressive focal mononuclear cell infiltration in the affected salivary and lacrimal glands. Lymphoma is the most severe complication of pSS, occurring in 4% to 5% of patients. Genetic studies identified an association with HLA and susceptibility genes in cytokine genes and genes involved in B-cell differentiation. Genetic variations may help explain why disease manifestations differ among patients and supports the hypothesis of certain distinct disease phenotypes.
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