How Protein Transmembrane Segments Sense the Lipid Environment

Nyholm, Thomas K.M.; Özdirekcan, Suat; Killian, J. Antoinette

doi:10.1021/bi061941c

Cited by 145 publications

(131 citation statements)

References 93 publications

(146 reference statements)

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“…An angle of 37°would allow the end of the FtsL/DivIC coiled-coil to make contact with the base of a ␤-domain 40 Å from the membrane. Note that tilt angles of this magnitude are not unheard of for transmembrane helices (48). Alternatively, the presence of a kink between the transmembrane segment and the extracellular coiled-coil of FtsL and DivIC cannot be excluded.…”

Section: Discussionmentioning

confidence: 97%

Central Domain of DivIB Caps the C-terminal Regions of the FtsL/DivIC Coiled-coil Rod

Masson

Kern

Gouëllec

et al. 2009

Journal of Biological Chemistry

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DivIB(FtsQ), FtsL, and DivIC(FtsB) are enigmatic membrane proteins that are central to the process of bacterial cell division. DivIB(FtsQ) is dispensable in specific conditions in some species, and appears to be absent in other bacterial species. The presence of FtsL and DivIC(FtsB) appears to be conserved despite very low sequence conservation. The three proteins form a complex at the division site, FtsL and DivIC(FtsB) being associated through their extracellular coiled-coil region. We report here structural investigations by NMR, small-angle neutron and x-ray scattering, and interaction studies by surface plasmon resonance, of the complex of DivIB, FtsL, and DivIC from Streptococcus pneumoniae, using soluble truncated forms of the proteins. We found that one side of the "bean"-shaped central ␤-domain of DivIB interacts with the C-terminal regions of the dimer of FtsL and DivIC. This finding is corroborated by sequence comparisons across bacterial genomes. Indeed, DivIB is absent from species with shorter FtsL and DivIC proteins that have an extracellular domain consisting only of the coiled-coil segment without C-terminal conserved regions (Campylobacterales). We propose that the main role of the interaction of DivIB with FtsL and DivIC is to help the formation, or to stabilize, the coiled-coil of the latter proteins. The coiled-coil of FtsL and DivIC, itself or with transmembrane regions, could be free to interact with other partners.

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Section: Discussionmentioning

confidence: 97%

Central Domain of DivIB Caps the C-terminal Regions of the FtsL/DivIC Coiled-coil Rod

Masson

Kern

Gouëllec

et al. 2009

Journal of Biological Chemistry

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“…At the same time the charge and polarity of E73 is strongly correlated with the dynamics and conformation of the membrane environment, suggesting that the dynamics of the lipids might be connected with global protein motions. This finding is interesting as lipid-protein interactions are known to be important for the structure and function of integral membrane proteins (47)(48)(49)(50)(51)(52). In particular, VDAC1 gating and ionic selectivity have been shown to be dependent on lipid composition (53).…”

Section: μS-ms Dynamics Are Significantly Increased For the N-terminamentioning

confidence: 89%

Functional dynamics in the voltage-dependent anion channel

Villinger

Briones

Giller

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

103

129

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The voltage-dependent anion channel (VDAC), located in the outer mitochondrial membrane, acts as a gatekeeper for the entry and exit of mitochondrial metabolites. Here we reveal functional dynamics of isoform one of VDAC (VDAC1) by a combination of solution NMR spectroscopy, Gaussian network model analysis, and molecular dynamics simulation. Micro-to millisecond dynamics are significantly increased for the N-terminal six β-strands of VDAC1 in micellar solution, in agreement with increased B-factors observed in the same region in the bicellar crystal structure of VDAC1. Molecular dynamics simulations reveal that a charge on the membrane-facing glutamic acid 73 (E73) accounts for the elevation of N-terminal protein dynamics as well as a thinning of the nearby membrane. Mutation or chemical modification of E73 strongly reduces the micro-to millisecond dynamics in solution. Because E73 is necessary for hexokinase-I-induced VDAC channel closure and inhibition of apoptosis, our results imply that microto millisecond dynamics in the N-terminal part of the barrel are essential for VDAC interaction and gating.membrane protein | molecular dynamics | NMR spectroscopy | protein-lipid interactions | structure D ynamics of proteins provide the essential link between structure and function. Membrane protein dynamics are gaining more attention due to an increasing number of high-resolution structures. A versatile experimental method for the study of membrane protein dynamics is NMR spectroscopy, providing atomic resolution information from nanoseconds to seconds (for an overview see ref. 1). In addition, when a three-dimensional structure is available, insight into fast dynamics of proteins, which occur on the nanosecond time scale, might be gained from molecular dynamics (MD) simulation and elastic network models (2, 3).NMR studies have revealed large conformational changes essential for the physiological function of α-helical membrane proteins, such as the interaction of phospholamban with effectors modulating heart muscle contractility (4, 5) and antimicrobial peptides adopting different conformations in membranes or solution (6, 7). Less well characterized are motions of outer membrane β-barrels. A pioneering solution NMR study revealed μs-ms interconversion of the catalytic loop of PagP between an excited and a nonexcited state, enabling both ligand binding and enzymatic catalysis (8). Nonenzymatic β-barrel channels exhibit more general dynamic features, such as loop flexibility and slow conformational exchange towards the extracellular barrel edges, altogether indicating relevance for substrate conductance and gating (9-11).The voltage-dependent anion channel (VDAC) is one of the few β-barrel membrane proteins, the structure of which has been determined to date (12-14). Serving as the major pass-through for metabolites between mitochondria and the cytosol (15), the highly abundant channel is regarded as a key regulator of cellular energy metabolism (16). Metabolite flow is regulated by a voltage-dependent conformational c...

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“…Moreover, the ER membrane has been reported to be thinner by some 5 Å than the plasma membrane because of the lower cholesterol content and/or the protein composition (20,21). If the TMD of LRP6 was oriented perpendicular to the plane of the ER membrane, the length of TMD of LRP6 would exceed the thickness of the membrane, thus leading to a so-called hydrophobic mismatch (22). This hydrophobic mismatch would presumably be detected by the ER quality control and lead to ER retention.…”

Section: Lrp6 Is Palmitoylated On a Juxtamembranous Cysteinementioning

confidence: 99%

Palmitoylation and ubiquitination regulate exit of the Wnt signaling protein LRP6 from the endoplasmic reticulum

Abrami

Kunz

Iacovache

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

150

175

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Canonical Wnt signaling is initiated by binding of Wnt proteins to members of the Frizzled family and subsequent complex formation with lipoprotein receptor-related proteins 5/6 (LRP5/6). Here, we show that LRP6 is palmitoylated on a juxtamembranous cysteine and that palmitoylation is required for exit from the endoplasmic reticulum (ER). We propose that palmitoylation serves to tilt the long, 23-residue transmembrane domain of LRP6 with respect to the plane of membrane to prevent a hydrophobic mismatch and subsequent recognition by the ER quality control. In support of this model, a palmitoylation-deficient LRP6 mutant could be rescued from ER retention by deletion of two to four residues in the transmembrane domain. Importantly, we found that palmitoylation-deficient LRP6 was retained in the ER by a completely novel monoubiquitinationdependent ER retention mechanism. Mutation of a specific lysine indeed abolished ubiquitination of palmitoylation-deficient LRP6 and led to a rescue from ER retention. Finally, at the cell surface, we found that interplay between palmitoylation and ubiquitination was necessary for efficient Wnt signaling.he signaling of Wnt plays a critical role in a variety of developmental and adult processes in all metazoan and in diseases such as cancer (1). Canonical Wnt signaling via ␤-catenin is transduced by two receptor families: the Frizzled proteins and lipoprotein receptor-related proteins (LRPs) 5 and 6. Wnt binds to Frizzled, which then associates with LRP5/6. The cytoplasmic domains of LRP5/6, upon receptor activation by Wnt proteins, recruit the cytosolic scaffold protein axin to the membrane, displacing it from the so-called destruction complex (containing axin, glycogen synthase kinase 3␤, Wilms tumor suppressor, and ␤-catenin) involved in the degradation of ␤-catenin by the proteasome (for review see ref.2). This rescue of ␤-catenin allows it to translocate into the nucleus and interact with T cell factor (TCF)/lymphoid enhancer factor to activate transcription (3). As a result, Wnt activates multiple intracellular cascades, leading to cell differentiation, proliferation, migration, and polarity.LRP6 is a type I membrane protein with a large, 1,351-aa extracellular domain, containing multiple ␤-propeller and EGF domains, and a 220-aa-long cytoplasmic tail. As all type I transmembrane proteins, LRP6 is synthesized with an Nterminal signal sequence that targets it to the endoplasmic reticulum (ER). Folding of the LRP6 ␤-propeller domains in the lumen of the ER requires the help of an ER-resident chaperone called mesoderm development candidate 2 (Mesd) in mammals and Boca in Drosophila (4, 5). In the absence of Mesd, LRP6 is retained in the ER and thus fails to reach the cell surface.Human LRP6 contains six cysteine residues in its cytoplasmic tail, which are potential sites for palmitoylation (6). This lipid can serve to tether soluble proteins to membranes but is also found attached to the cytoplasmic domains of membrane proteins often close to the transmembrane region (7). The f...

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How Protein Transmembrane Segments Sense the Lipid Environment

Cited by 145 publications

References 93 publications

Central Domain of DivIB Caps the C-terminal Regions of the FtsL/DivIC Coiled-coil Rod

Central Domain of DivIB Caps the C-terminal Regions of the FtsL/DivIC Coiled-coil Rod

Functional dynamics in the voltage-dependent anion channel

Palmitoylation and ubiquitination regulate exit of the Wnt signaling protein LRP6 from the endoplasmic reticulum

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