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2 edition of Aberrant transmembrane helix-helix interactions as a biophysical cause of human disease. found in the catalog.

Aberrant transmembrane helix-helix interactions as a biophysical cause of human disease.

Anthony William Partridge

Aberrant transmembrane helix-helix interactions as a biophysical cause of human disease.

by Anthony William Partridge

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Published .
Written in English


About the Edition

Mutations that alter transmembrane (TM) helix-helix interactions can result in disease by compromising protein structure/function. Recent reports showed that TM-embedded polar residues play powerful roles in TM domain (TMD) folding by forming interhelical H-bonds (reviewed in (Partridge et al., 2002b)). Thus, mutations involving these species could result in disease by disrupting the pattern of native electrostatic links. To explore this possibility, we performed a statistical analysis of the phenotypic missense mutations listed in the human gene mutation database. We found that both polar to non-polar and non-polar to polar mutations are more often associated with disease in TMDs compared to soluble domains. This suggests that, in TMDs, both the disruption of native structure-stabilizing H-bonds and the formation of non-native structure-destabilizing H-bonds are frequent causes of human disease. To experimentally investigate these concepts, we developed a peptide-based system for the study of TM helix-helix interactions. This "Lys-tagged" approach involves the addition of several Lys residues to both the N- and C-termini of a single TM helix. The resulting species are water-soluble, a property that greatly facilitates their purification and characterization. Furthermore, such peptides retain the ability to insert into membrane-mimetic environments to assume their native-like secondary and tertiary structures. Using such peptides, we showed that when applied to TM4 from the cystic fibrosis conductance regulator, the apolar to polar phenotypic mutation V232D induces the formation of multiple non-covalent oligomeric states through the formation of an interhelical H-bonding network. The powerful effect of this mutation is context-specific, since randomized sequences containing the analogous interhelical H-bonding components could not form similar oligomeric assemblies. Studies on the TM helix from myelin protein zero (PO) and its phenotypic mutation show that an apolar to polar mutation can similarly disrupt native state oligomeric states through mechanisms not involving interhelical H-bonds. We demonstrate that the native P0-TM helix forms a tetrameric bundle and that the phenotypic mutation G163R prevents this assembly through steric clash interactions. The research presented suggests that the proper packing of TM helices is vital to protein function and that TM-embedded mutations involving polar residues manifest their deleterious effects through a variety of mechanisms.

The Physical Object
Pagination144 leaves.
Number of Pages144
ID Numbers
Open LibraryOL20339065M
ISBN 10061291691X

The human prion protein (PrP), which is the root cause of several related neurodegenerative disorders, exists in both a membrane-anchored glycosylphosphatidylinositol (GPI) modified form and a form that contains a single TM helix. Interestingly, the TM form of PrP .   HIV-1 Vpu, also a transmembrane protein, counteracts the restriction by tetherin , through a mechanism that depends on a direct interaction between the viral and host proteins ,

  This seminal paper describes a specific interaction between Csphingomyelin and the transmembrane protein p24, by which protein dimerization and vesicle trafficking are affected. D Grabulovski, J Bertschinger, in Drug Discovery and Development (Second Edition), SH3 domain of Fyn kinase (Fynomers) Fyn kinase is a 59 kDa member of the Src family of tyrosine kinases (Cooke and Perlmutter, ; Resh, ).As a result of alternative splicing, the Fyn protein is expressed as two isoforms, differing in approximately 50 amino acids in a region between their SH2 and.

The interactions of their transmembrane domains (TMDs) play a key role in dimerization and signaling. Fibroblast growth factor receptor 3 (FGFR3) is of interest as a GR mutation in its TMD is the underlying cause of ∼99% of the cases of achondroplasia, the most common form of human dwarfism. Ion Channel Function. Fundamentally, an ion channel acts as an energetically favorable pathway for small charged molecules (ions) to pass through the cell membrane (Hille ).Ion channels are integral transmembrane proteins that exist as oligogenic macromolecular complexes including a pore-forming alpha subunit and modulatory and accessory subunits (Sharman et al. ; Alexander et al. ).


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Aberrant transmembrane helix-helix interactions as a biophysical cause of human disease by Anthony William Partridge Download PDF EPUB FB2

The GlyArg mutation was created for this work by changing nucleotide from G to A in the transmembrane domain of the construct, as described in Materials and Methods. The interactions were measured in plasma membrane derived vesicles produced from human embryonic kidney T (HEKT) by: Many transmembrane helices contain serine and/or threonine residues whose side chains form intrahelical H-bonds with upstream carbonyl oxygens.

Here, we investigated the impact of threonine side-chain/main-chain backbonding on the backbone dynamics of the amyloid precursor protein transmembrane helix.

This helix consists of a N-terminal dimerization region and a C-terminal Cited by: Using the Human Gene Mutation Database of proteins (including 80 membrane proteins) associated with human disease, we compared the relative phenotypic propensity to cause disease of the The human ERBB2 is a transmembrane signaling tyrosine kinase receptor, which seems an ideal target of human WNT16B: the secreted growth factor possibly causing transmembrane.

Helix-helix interactions play a central role in the folding and assembly of integral α-helical membrane proteins and are fundamentally dictated by the amino acid sequence of the TM domain.

The human adenosine A(2A) receptor (A(2A)R) is an integral membrane protein and a member of the G-protein-coupled receptor (GPCR) superfamily, characterized by seven transmembrane (TM) helices.

A Role for Aberrant α-Syn–Membrane Interactions in Neurotoxicity. Aberrant α-syn–membrane interactions may play a role in various mechanisms of α-syn neurotoxicity. As one example, α-syn has been shown to interfere with trafficking between the endoplasmic reticulum (ER) and Golgi, a defect that precedes ER stress.

Specific helix-helix interactions between the single-span transmembrane domains of receptor tyrosine kinases are believed to be important for their lateral dimerization and signal transduction.

This may promote a hydrophobic interaction/cluster formation among RL, I33 and V69 thereby altering the helix-helix interaction and ultimate protein conformation. Substitution of R with cysteine in RC variation could also cause destabilization of interactions among RC, F72, V69 and S68 (not shown).

The functional deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR), a plasma membrane chloride channel, leads to the development of cystic fibrosis.

The deletion of a phenylalanine at residue (Fdel) is the most common cause of CFTR misfolding leading to the disease. The Fdel misfolding originates in the first nucleotide-binding domain (NBD1), which induces a. C. Escher, F. Cymer, D. SchneiderTwo GxxxG-like motifs facilitate promiscuous interactions of the human erbb transmembrane domains.

Dramatic advances in the understanding of the molecular mechanisms of membrane receptor activation for several prototypic members of different families of receptors have taken place during the past 2–3 years.

The new structures of receptor fragments or full-length receptors in different conformations have been reviewed previously in light of the large bodies of available structure–function. Transmembrane Helix−Helix Interactions: Comparative Simulations of the Glycophorin A Dimer.

Biochemistry45 (48), DOI: /bi Kevin R. MacKenzie. Folding and Stability of α-Helical Integral Membrane Proteins. Physical - chemical models of RTK activation.

We and others have proposed that RTK activation can be described with physical-chemical models which account for dimerization, ligand binding and phosphorylation (12–16).Such models have been shown to give an adequate description of RTK phosphorylation data, despite their simplicity.

Manni et al. describe the role of the VEGF receptor transmembrane domain in receptor signaling. The authors correlate biochemical analyses on mutant receptors carrying dimerization-promoting transmembrane domains with structural data obtained by NMR. Introduction. The transmembrane domains (TMDs) of integral membrane proteins are mostly composed of hydrophobic amino acids.

Many of them also contain polar amino acids that contribute to helix-helix interactions, cofactor binding, etc. ().That polar amino acids serve structural roles supporting protein function is indicated by the fact that mutations of Ser, Thr, and Cys within. The presence of disease-causing mutations in the CFTR gene leads to an absence of one or more of these activities.

Such loss-of-function effects can arise from one or more of several distinct mechanisms including direct effects on channel function (12 – 14), effects on regulation (15), or effects that cause aberrant folding (16, Intramembrane cleavage of the β-amyloid precursor protein C99 substrate by γ-secretase is implicated in Alzheimer’s disease pathogenesis.

Biophysical data have suggested that the N-terminal part of the C99 transmembrane domain (TMD) is separated from the C-terminal cleavage domain by a di-glycine hinge. Because the flexibility of this hinge might be critical for γ-secretase cleavage, we.

Biophysical and structural investigations are presented with a focus on the membrane lipid interactions of cationic linear antibiotic peptides such as magainin, PGLa, LL37, and melittin.

Observations made with these peptides are distinct as seen from data obtained with the hydrophobic peptide alamethicin. The cationic amphipathic peptides predominantly adopt membrane alignments parallel to the. the formation of helix–helix contacts. This hypothesis is consistent with biochemical and biophysical studies of bacteriorhodopsin, a 7-TM helical bundle [3–5].In particular, bacteriorhodopsin can be refolded in vitro from fragments corresponding to individual helices.

Abstract. Cystic fibrosis is caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR), commonly the deletion of residue Phe (DeltaF) in the first nucleotide-binding domain (NBD1), which results in a severe reduction in the population of .The {Delta}F mutation in nucleotide-binding domain 1 (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) is the predominant cause of cystic fibrosis.

Previous biophysical studies on human F and {Delta}F domains showed only local structural changes restricted to residues and only minor differences in folding. Following ectodomain shedding by β-secretase, successive proteolytic cleavages within the transmembrane sequence (TMS) of the amyloid precursor protein (APP) catalyzed by γ-secretase result in the release of amyloid-β (Aβ) peptides of variable length.

Aβ peptides with 42 amino acids appear to be the key pathogenic species in Alzheimer’s disease, as they are believed to initiate .