The dimerization motif of the glycophorin A transmembrane segment in membranes: Importance of glycine residues

Brosig, Bettina; Langosch, Dieter

doi:10.1002/pro.5560070423

Cited by 215 publications

(203 citation statements)

References 21 publications

Supporting

Mentioning

191

Contrasting

Order By: Relevance

“…In the heterodimerization model, we consider the three linked dimerization equilibria; homodimerizations of species A and B are defined by two homomeric dissociation constants (K a and K b , respectively), and the third equilibrium is defined by a heteromeric dissociation constant (K ab ) (eqs [6][7][8] By experimental design, the total concentration of the A species is always equal to that of the B species; this facilitates the analysis. Using eqs 10 and 11, which follow from this condition, and combining with eq 7, we obtain a secondorder polynomial expansion (eq 12).…”

Section: Methodsmentioning

confidence: 99%

A Dimerization Hierarchy in the Transmembrane Domains of the HER Receptor Family

2007

View full text Add to dashboard Cite

Bitopic membrane proteins offer an opportunity for studying transmembrane domain interactions without the structural complexity inherent to multitopic integral membrane proteins. To date, only homomeric associations have been extensively studied quantitatively. Here we propose to assess the thermodynamics of heteromeric associations, which opens the way to investigating specificity and selectivity. A very interesting system of biological relevance with single transmembrane domains possibly involved in interactions with different partners is the EGFR receptor family. The four members, all tyrosine kinase receptors, are involved in an interaction network that potentially leads to a complete set of homoand heterodimers, ideally suited to such a study. Furthermore, the transmembrane domains of these receptors have been previously implicated in their function in the past by mutations in the transmembrane domain leading to constitutive activation. We demonstrate, using a fluorescence-based measurement of interaction energies, a hierarchy of transmembrane domain interactions ranging from a noninteractive pair to strong dimerization. We propose a structural model based on the crystal structure of the EGFR dimer, to show how the dimeric structure favors these interactions. The correlation we observe between transmembrane domain and whole receptor interaction hierarchies opens a new perspective, suggesting a role for transmembrane receptor domains in the modulation of receptor signaling.

show abstract

Section: Methodsmentioning

confidence: 99%

A Dimerization Hierarchy in the Transmembrane Domains of the HER Receptor Family

2007

View full text Add to dashboard Cite

show abstract

“…Oligomerization-The GXXXG motif, in which two glycine residues are separated by any three amino acids on a helical framework, is recognized as a "dimerization motif," because it mediates the assembly of two transmembrane helices (35)(36)(37). Its presence within the TMD of VAP-B ( 235 GXXXG 239 ) prompted us to investigate its contribution to VAP-B oligomerization using mutagenesis studies and cross-linking experiments in intact cells.…”

Section: The Gxxxg Motif In the Tmd Is Insufficient To Drive Vap-bmentioning

confidence: 99%

Structural Requirements for VAP-B Oligomerization and Their Implication in Amyotrophic Lateral Sclerosis-associated VAP-B(P56S) Neurotoxicity

Kim

Leal

Halevy

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

The integral endoplasmic reticulum (ER)-membrane protein VAP-B interacts with various lipid-transfer/binding proteins containing an FFAT motif through its N-terminal MSP domain. A genetic mutation within its MSP domain, P56S, was identified in familial forms of motor neuron diseases. This mutation induces the formation of insoluble VAP-B(P56S) protein aggregates by an unknown mechanism. In this study, we defined the structural requirements for VAP-B oligomerization and demonstrated their contribution for VAP-B(P56S) aggregation and neurotoxicity. We show that the oligomerization of VAP-B is mainly mediated by its coiled-coil domain and that the GXXXG dimerization motif within the transmembrane domain mediates transmembrane domains self-association but is insufficient to drive VAP-B oligomerization. We further show that the oligomerization of the wild-type VAP-B is independent of its MSP domain. However, we found that the P56S mutation induces conformational changes within the MSP domain and facilitates its propensity to aggregate by exposing hydrophobic patches to the solvent. These conformational changes have no direct effect on FFAT binding. Rather, they enhance VAP-B(P56S) oligomerization driven by the combined contributions of the coiled-coil and the transmembrane domains, thereby preventing accessibility to FFAT-binding site, facilitating the production of VAP-B(P56S)-insoluble aggregates and consequently its neurotoxicity. These results shed light on the mechanism by which VAP-B(P56S) aggregates are formed and induce familial motor neuron diseases.Protein aggregation and inclusion body formation are common pathological features of many neurological disorders including Huntington disease, Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis (ALS) 3 (1, 2).ALS is a fatal neurodegenerative disorder involving progressive loss of motor neurons in the cerebral cortex, brain stem, and spinal cord (3). Approximately 10% of the cases are familial, of which 20% are caused by dominantly inherited mutations in the Cu/Zn-superoxide dismutase (SOD) gene (4, 5). Recently, mutations in other genes, including the human VAP-B, have been identified in ALS patients (6 -8).The mutation in VAP-B substitutes a highly conserved proline residue at position 56 by a serine (P56S) and is associated with three forms of human motor neuron diseases: a late-onset spinal muscular atrophy, an atypical ALS type 8, and a typical severe ALS with rapid progression (7, 9). Atypical ALS type 8 is an autosomal dominant slowly progressive disorder characterized by fasciculation, cramps, and postural tremor. It is currently unknown how this P56S mutation induces motor neuron degeneration. Nevertheless, recent studies suggest that the VAP-B(P56S) mutant acts in a dominant fashion through dimerization with the wild-type protein and inactivating the heterodimer and that expression of the VAP-B(P56S) mutant induces the formation of insoluble protein aggregates (7, 10 -15). Indeed, co-expression studies suggest that wild-type VAP-B is...

show abstract

“…In several studies, the minimal GpA dimerization motif has been identified, and dimerization is driven by a seven amino acid motif LIxxGVxxGVxxT [9]. While the two glycine residues in a distance of four (GxxxG-motif) appear to be of special importance for dimerization and dimer stability [8][9][10], all seven amino acids are directly involved in helix-helix interactions and align at the contact surface. However, interactions of the GpA TM helices are complex and not only modulated by the sequence context but also by the lipid and/or detergent environment [2,11,12].…”

Section: Introductionmentioning

confidence: 99%

Six amino acids define a minimal dimerization sequence and stabilize a transmembrane helix dimer by close packing and hydrogen bonding

Weber

Schneider

2013

FEBS Letters

View full text Add to dashboard Cite

Edited by Richard CogdellKeywords: Cytochrome b 559 Dimerization motif Transmembrane Helix-helix interaction Sequence context a b s t r a c t Distinct amino acid sequences have been described to mediate oligomerization of transmembrane a-helices. However, as the sequence context is crucial to determine specificity in transmembrane helix-helix interaction, the question arises how small a sequence can be without losing specificity. In the present analysis, six amino acids have been identified in the PsbF transmembrane helix dimer, which form the contact region of two interacting helices and are directly involved in helix-helix interactions. However, individual amino acids within the complex sequence pattern only together ensure sequence specificity of the analyzed transmembrane helix-helix interactions by mediating close packing and inter-helical hydrogen bonding. Structured summary of protein interactions:psbF and psbF physically interact by lex-a dimerization assay (View Interaction: 1,2,3,4,5)

show abstract

The dimerization motif of the glycophorin A transmembrane segment in membranes: Importance of glycine residues

Cited by 215 publications

References 21 publications

A Dimerization Hierarchy in the Transmembrane Domains of the HER Receptor Family

A Dimerization Hierarchy in the Transmembrane Domains of the HER Receptor Family

Structural Requirements for VAP-B Oligomerization and Their Implication in Amyotrophic Lateral Sclerosis-associated VAP-B(P56S) Neurotoxicity

Six amino acids define a minimal dimerization sequence and stabilize a transmembrane helix dimer by close packing and hydrogen bonding

Contact Info

Product

Resources

About