Revista virtual interactiva atípica

Esta revista tiene como propósito, plantearle a los jóvenes de Bogotá, planes de uso del tiempo libre, frente a cualquier temática, utilizando como valor agregado,sobre las otras revistas, una sección dedicada a registrar historias, curiosidades y sucesos fuera de lo común, cosas insólitas no solo de Bogotá, también en el mundo

Reconstructing the Population Genetic History of the Caribbean

The Caribbean basin is home to some of the most complex interactions in recent history among previously diverged human populations. Here, by making use of genome-wide SNP array data, we characterize ancestral components of Caribbean populations on a sub-continental level and unveil fine-scale patterns of population structure distinguishing insular from mainland Caribbean populations as well as from other Hispanic/Latino groups. We provide genetic evidence for an inland South American origin of the Native American component in island populations and for extensive pre-Columbian gene flow across the Caribbean basin. The Caribbean-derived European component shows significant differentiation from parental Iberian populations, presumably as a result of founder effects during the colonization of the New World. Based on demographic models, we reconstruct the complex population history of the Caribbean since the onset of continental admixture. We find that insular populations are best modeled as mixtures absorbing two pulses of African migrants, coinciding with early and maximum activity stages of the transatlantic slave trade. These two pulses appear to have originated in different regions within West Africa, imprinting two distinguishable signatures in present day Afro-Caribbean genomes and shedding light on the genetic impact of the dynamics occurring during the slave trade in the Caribbean.Comment: 26 pages, 6 figures, and supporting informatio

Design, Structure and Applications of Collagen-Mimetic Peptides

The collagen triple helix is a unique protein fold found in all domains of life where is has diverse roles from imparting structure and strength to tissue, to initiating an immune response. While many factors affecting the structure and stability of the triple helix have previously been elucidated, much remains unknown about collagen. Using collagen-mimetic peptides, it is possible to investigate the molecular structure of the triple helix, determine new pairwise interactions of amino acids, characterize disease models and also create designer collagens that will preferentially hybridize to natural collagen-rich tissue. First a selective labeling scheme is used to thoroughly characterize a well-folded triple helical region, and then to determine the degree of localized unfolding at the N- and C-termini. Though terminal fraying extends farther than previously shown, small sequence alterations at the N-terminus have a drastic influence on local stability (~15C). Next, a single register heterotrimeric mimic of the type I collagen disease Osteogenesis Imperfecta is used to investigate single point glycine mutations in the B chain, the A chain or both chains. Unlike past reports, a combination of NMR analysis and molecular modelling is used to generate structures of the mutated helices and visualize the underlying mechanisms of helix destabilization in OI. For the first time it is proven that these mutations cause compositional as well as structural disruptions. Additionally, while several hundred pairwise interactions are possible in the triple helix, to date only two interactions are wellunderstood and commonly incorporated into CMP design. To expand on the library of known interactions, the structure and stability of helices containing serine, threonine, phospho-serine and phospho-threonine were investigated. Notably, when phospho-serine is paired with lysine a new highly stabilizing (49.5 C) axial interaction is possible. Finally, the design of a collagen type II targeting peptide is described, and NMR, CD and confocal microscopy are used to investigate the hybridization of the synthetic peptide with the natural partner strands

Control of collagen triple helix stability by phosphorylation

The phosphorylation of the collagen triple helix plays an important role in collagen synthesis, assembly, signaling, and immune response, although no reports detailing the effect this modification has on the structure and stability of the triple helix exist. Here we investigate the changes in stability and structure resulting from the phosphorylation of collagen. Additionally, the formation of pairwise interactions between phosphorylated residues and lysine is examined. In all tested cases, phosphorylation increases helix stability. When charged-pair interactions are possible, stabilization via phosphorylation can play a very large role, resulting inasmuch as a 13.0 °C increase in triple helix stability. Two-dimensional NMR and molecular modeling are used to study the local structure of the triple helix. Our results suggest a mechanism of action for phosphorylation in the regulation of collagen and also expand upon our understanding of pairwise amino acid stabilization of the collagen triple helix

Synthetic, register-specific, AAB heterotrimers to investigate single point glycine mutations in osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a disease caused primarily by mutations of glycine in the standard (Xaa-Yaa-Gly)n repeat of a type I collagen triple helix. Type I collagen is an AAB heterotrimer which means that, depending on whether the A or B chain is mutated, the glycine substitution will appear once or twice. In this work we use designed axial charged pairs to self-assemble an AAB triple helix with controlled composition and register. We then substitute a single glycine of the B chain with alanine, serine, valine, aspartate, or arginine and assess the impact on the structure and folding of this OI mimic by CD, NMR, and restraint-guided modeling. We find that alanine and serine substitutions are tolerated, resulting in localized disruptions to the triple helix structure, while bulkier amino acids result in alternatively folded structures. This work demonstrates the potential of axial charged pairs to control the structure of low stability triple helices and also helps to elucidate the structure and folding challenges associated with OI-type mutations in collagen

Revista virtual interactiva atípica

Esta revista tiene como propósito, plantearle a los jóvenes de Bogotá, planes de uso del tiempo libre, frente a cualquier temática, utilizando como valor agregado,sobre las otras revistas, una sección dedicada a registrar historias, curiosidades y sucesos fuera de lo común, cosas insólitas no solo de Bogotá, también en el mundo

Comparative NMR analysis of collagen triple helix organization from N- to C-termini

The collagen triple helix consists of three supercoiled solvent-exposed polypeptide chains, and by dry weight it is the most abundant fold in mammalian tissues. Many factors affecting the structure and stability of collagen have been determined through the use of short synthetically prepared peptides, generally called collagen-mimetic peptides (CMPs). NMR (nuclear magnetic resonance spectroscopy) investigations into the molecular structure of CMPs have suffered from large amounts of signal overlap and degeneracy because of collagen’s repetitive primary sequence, the close and symmetric packing of the three chains and the identical peptide sequences found in homotrimers. In this paper a peptide library is prepared in which a single isotopic 15N-Gly label is moved sequentially along the peptide backbone. Our approach allows for a more explicit examination of local topology than available in past reports. This reveals larger regions of disorder at the C-terminus than previously detected by crystallographic or NMR studies, and here C-terminal fraying is seen to extend for six amino acids in a (POG)10 sequence. Furthermore, small sequence changes at the N-terminus greatly influence the degree of this localized disorder and may be useful in the future design of CMPs to maximize collagen’s interstrand hydrogen bonding pattern. Our approach and data serves as a reference for future CMP characterizations to determine the quality and extent of folding

Synthetic, Register-Specific, AAB Heterotrimers to Investigate Single Point Glycine Mutations in Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a disease caused primarily by mutations of glycine in the standard (Xaa-Yaa-Gly)_<i>n</i> repeat of a type I collagen triple helix. Type I collagen is an AAB heterotrimer which means that, depending on whether the A or B chain is mutated, the glycine substitution will appear once or twice. In this work we use designed axial charged pairs to self-assemble an AAB triple helix with controlled composition and register. We then substitute a single glycine of the B chain with alanine, serine, valine, aspartate, or arginine and assess the impact on the structure and folding of this OI mimic by CD, NMR, and restraint-guided modeling. We find that alanine and serine substitutions are tolerated, resulting in localized disruptions to the triple helix structure, while bulkier amino acids result in alternatively folded structures. This work demonstrates the potential of axial charged pairs to control the structure of low stability triple helices and also helps to elucidate the structure and folding challenges associated with OI-type mutations in collagen

Glycine Substitutions in Collagen Heterotrimers Alter Triple Helical Assembly

Osteogenesis imperfecta typically results from missense mutations in the collagen genome where the required glycine residues are replaced with another amino acid. Many models have attempted to replicate the structure of mutated collagen on the triple helix level. However, composition and register control of the triple helix is complicated and requires extreme precision, especially when these destabilizing mutations are present. Here we present mutations to a composition- and register-controlled AAB helix where one of the requisite glycines in the A chain of the triple helix is changed to serine or alanine. We see a loss of compositional control when the A chain is mutated, resulting in an A′BB composition that minimizes the number of mutations included in the triple helix. However, when both A and B chains are mutated and no nonmutated peptide chains are available, the designed A′A′B′ composition is reestablished. Our work shows the ability of the mutations to influence and alter the composition and register of the collagen triple helix