Side-Chain to Main-Chain Hydrogen Bonding Controls the Intrinsic Backbone Dynamics of the Amyloid Precursor Protein Transmembrane Helix

Scharnagl, Christina; Pester, Oxana; Hornburg, Philipp; Hornburg, Daniel; Götz, Alexander; Langosch, Dieter

doi:10.1016/j.bpj.2014.02.013

Cited by 34 publications

(95 citation statements)

References 54 publications

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“…How could our present findings explain this impact of T43I? Previous MD simulations showed that the loss of the T43 side‐chain/main‐chain H‐bonding in a T43 V mutant increases the relative movements of TM−N versus TM−C at the G 37 G 38 hinge . Thereby, a very subtle local destabilization, as detected here by increasing amide exchange kinetics, can translate into profound changes of global helix dynamics.…”

Section: Figuresupporting

confidence: 51%

“…For example, the T43I (‘Austrian’) mutation (Aβ numbering) is thought to lead to an extremely early mean age‐of‐onset (36 y) by strongly increasing the Aβ42/Aβ40 ratio . The side‐chain of T43 is H‐bonded to the main chain carbonyl oxygen of V39 and controls the repertoire of TM−N versus TM−C bending motions as indicated by molecular dynamics (MD) simulations . It is unclear, however, how the loss of this H‐bond in the disease‐causing T43I mutant is connected to the flexibility of the hinge.…”

Section: Figurementioning

confidence: 99%

“…Here, we investigated the effects of the T43I mutation on synthetic peptides representing the complete predicted APP TMD helix (A28‐55 wild‐type and T43I) (Figure A) in 80 % (v/v) trifluoroethanol (TFE) /water. Due to the similar polarities of TFE (ϵ=8.55) and protein interiors (ϵ ∼4 to ∼12 corresponding to dry and internally solvated proteins, respectively) we consider 80 % TFE as a reasonable mimic of the aqueous environment within the catalytic cleft of presenilin as done previously , , . Presenilin represents the catalytic subunit of γ‐secretase.…”

Section: Figurementioning

confidence: 99%

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The Impact of the ‘Austrian’ Mutation of the Amyloid Precursor Protein Transmembrane Helix is Communicated to the Hinge Region

et al. 2016

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The transmembrane helix of the amyloid precursor protein is subject to proteolytic cleavages by γ‐secretase at different sites resulting in Aβ peptides of different length and toxicity. A number of point mutations within this transmembrane helix alter the cleavage pattern thus enhancing production of toxic Aβ peptide species that are at the root of familial Alzheimer's disease. Here, we investigated how one of the most devastating mutations, the ‘Austrian’ mutation T43I, affects this transmembrane helix. Site‐resolved deuterium/hydrogen amide exchange experiments reveal that the mutation destabilizes amide hydrogen bonds in the hinge which connects dimerization and cleavage regions. Weaker intrahelical hydrogen bonds at the hinge may enhance helix bending and thereby affect recognition of the transmembrane substrate by the enzyme and/or presentation of its cleavage sites to the catalytic cleft.

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Section: Figuresupporting

confidence: 51%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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The Impact of the ‘Austrian’ Mutation of the Amyloid Precursor Protein Transmembrane Helix is Communicated to the Hinge Region

et al. 2016

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“…Intrinsic substrate TMH properties that provide conformational flexibility such as the di-glycine hinge near the middle of the APP TMH have also been shown to play an important role for cleavage 46 . Although hydrogen-deuterium exchange experiments showed that the cleavage site region in APP is generally stable with respect to local helix flexibility [46][47][48][49] , MD simulations suggested that changes in bending and rotational motions, i.e. in the global flexibility, mediated by this hinge are critical for correct presentation of the cleavage site domain to the active site 46 .…”

Section: Discussionmentioning

confidence: 99%

Intramembrane cleavage of TREM2 is determined by its intrinsic structural dynamics

Steiner¹,

Schlepckow

Brunner

et al. 2019

Preprint

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words, 1027 characters)Sequence variants of the microglial expressed TREM2 (triggering receptor expressed on myeloid cells 2) are a major risk factor for late onset Alzheimer's disease. TREM2 requires a stable interaction with DAP12 in the membrane to initiate signaling, which is terminated by TREM2 ectodomain shedding and subsequent intramembrane cleavage by g-secretase. To understand the structural basis for the specificity of the intramembrane cleavage event, we determined the solution structure of the TREM2 transmembrane helix (TMH). Due to the presence of a charged amino acid in the membrane region the TREM2-TMH adopts a kinked structure with increased flexibility. Charge removal leads to TMH stabilization and reduced dynamics, similar to its structure in complex with DAP12. Strikingly, these dynamical features perfectly correlate with the site of the initial g-secretase cleavage event. These data suggest an unprecedented cleavage mechanism by g-secretase where flexible TMH regions are identified to initiate substrate cleavage.Single transmembrane helices remain a major challenge for structure determination approaches since they are highly flexible and therefore not suitable for crystallization. Solution NMR offers the advantage to study these dynamic domains in different membrane mimetics in solution and to obtain

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“…47). Threonine residues in α-helices, in particular in hydrophobic environments, often induce helical kinks, which could facilitate the repositioning of the finger helix (Cao and Bowie, 2012;Scharnagl et al, 2014).…”

Section: Figure 44mentioning

confidence: 99%

Structural Studies of Biopolymer Membrane Transport

Morgan¹

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The selective transport of specific substrates across the membrane is an essential part of biology.Organisms have evolved a basic mechanism for the transport of ions and small molecule such as sugars across the membrane. This mechanism is termed 'alternating access' and involves the alternating exposure of a substrate-binding site to either side of the membrane. While the molecular details of 'alternating access' have been revealed for a number of different transporters, this scheme seems infeasible for the transport of long biopolymers such as nucleic acids, proteins, and polysaccharides because 'alternating access' requires that the transporter forms a binding site that is large enough to bind the entire substrate. Here, I present novel data addressing the transport mechanism for two bacterial biopolymer transporter proteins: Bacterial Cellulose Synthase which synthesizes and secretes the polysaccharide, cellulose; and PrtD, an ABC transporter which is involved in the secretion of an extracellular protease.Cellulose is a linear polymer of glucose units that forms a major component of plant cell walls as well as many bacterial biofilms. In bacteria, the components required for cellulose biosynthesis are encoded in a single operon minimally made up of the genes bcsA, bcsB, bcsC, and bcsZ. BcsA is an integral inner-membrane (IM) glycosyltransferase enzyme that is responsible for coupling the synthesis of cellulose with its transport across the IM. BcsB is a periplasmic protein with Cterminal IM anchor, and BcsB forms a complex with BcsA (BcsA-B) that is sufficient for in vitro cellulose synthesis. BcsZ is a periplasmic cellulase enzyme, and BcsC is an outer-membrane β-barrel that presumably forms a pore for the cellulose polymer to cross the outer membrane.iii BcsA-B activity is stimulated by the bacterial signaling molecule, cyclic-di-GMP (c-di-GMP), which is a key regulator of biofilm formation. I present crystal structures of the c-di-GMP-bound BcsA-B complex in the presence and absence of UDP, a competitive inhibitor and substrate mimic. The structures reveal that c-di-GMP releases an auto-inhibited state of the enzyme. A salt bridge stabilizes one of the signature c-di-GMP-binding Arg residues in a position to tether a conserved 'gating loop' in front of the active site. The binding of c-di-GMP releases the tether and allows substrate to access the active site. Additionally, the UDP-bound structure reveals an additional role for the 'gating loop' in coordinating substrate at the active site. Functional experiments confirm the structural interpretation by revealing that disruption of the auto-inhibitory salt bridge by mutagenesis generates a constitutively-active cellulose synthase. The mechanistic insights presented here represent the first examples of how c-di-GMP allosterically modulates enzymatic functions.To address the mechanism by which BcsA-B transports cellulose across the IM, I use in crystallo enzymology with the c-di-GMP-bound BcsA-B crystals. Because crystallized BcsA-B is catalytically a...

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Side-Chain to Main-Chain Hydrogen Bonding Controls the Intrinsic Backbone Dynamics of the Amyloid Precursor Protein Transmembrane Helix

Cited by 34 publications

References 54 publications

The Impact of the ‘Austrian’ Mutation of the Amyloid Precursor Protein Transmembrane Helix is Communicated to the Hinge Region

The Impact of the ‘Austrian’ Mutation of the Amyloid Precursor Protein Transmembrane Helix is Communicated to the Hinge Region

Intramembrane cleavage of TREM2 is determined by its intrinsic structural dynamics

Structural Studies of Biopolymer Membrane Transport

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