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

We synthesized “glyco-arylopeptides”, whose folding structure significantly changes depending on the kind of saccharide in their side chain. The saccharide moiety interacts with the main chain via hydrogen bonding, and the non-natural polypeptides form two well-defined architectures—(P)-31- and (M)-41-helices—depending on the length of the saccharide chains and even the configuration of a single stereo-genic center in the epimers.

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Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals

eLife ◽

10.7554/elife.23961 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 35

Author(s):

Ho Yee Joyce Fung ◽

Szu-Chin Fu ◽

Yuh Min Chook

Keyword(s):

Hydrogen Bonding ◽

Crystal Structures ◽

Nuclear Export ◽

Main Chain ◽

Side Chain ◽

Large Array ◽

Structural Element ◽

Binding Groove ◽

Nuclear Export Receptor ◽

Hydrophobic Anchor

Nuclear export receptor CRM1 binds highly variable nuclear export signals (NESs) in hundreds of different cargoes. Previously we have shown that CRM1 binds NESs in both polypeptide orientations (Fung et al., 2015). Here, we show crystal structures of CRM1 bound to eight additional NESs which reveal diverse conformations that range from loop-like to all-helix, which occupy different extents of the invariant NES-binding groove. Analysis of all NES structures show 5-6 distinct backbone conformations where the only conserved secondary structural element is one turn of helix that binds the central portion of the CRM1 groove. All NESs also participate in main chain hydrogen bonding with human CRM1 Lys568 side chain, which acts as a specificity filter that prevents binding of non-NES peptides. The large conformational range of NES backbones explains the lack of a fixed pattern for its 3-5 hydrophobic anchor residues, which in turn explains the large array of peptide sequences that can function as NESs.

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Charged histidine affects alpha-helix stability at all positions in the helix by interacting with the backbone charges

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.90.23.11337 ◽

1993 ◽

Vol 90 (23) ◽

pp. 11337-11340 ◽

Cited By ~ 63

Author(s):

K M Armstrong ◽

R L Baldwin

Keyword(s):

Hydrogen Bonding ◽

Central Region ◽

Main Chain ◽

Alpha Helix ◽

Dipole Interaction ◽

Major Effect ◽

Side Chain ◽

Histidine Residue ◽

Helix Stability

To determine whether a charged histidine side chain affects alpha-helix stability only when histidine is close to one end of the helix or also when it is in the central region, we substitute a single histidine residue at many positions in two reference peptides and measure helix stability and histidine pKa. The position of a charged histidine residue has a major effect on helix stability in 0.01 M NaCl: the helix content of a 17-residue peptide is 24% when histidine is at position 3 compared to 76% when it is at position 17. This dependence of helix content on histidine position decreases sharply in 1 M NaCl, as expected for counterion screening of the charge-helix dipole interaction. Results at interior positions indicate that the position of a charged histidine residue affects helix stability at these positions. Unexpectedly high values of the helix content are found when either neutral or charged histidine is at one of the last three C-terminal positions, suggesting that either form can stabilize an isolated helix by hydrogen bonding to a main-chain CO group.

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Influence of hydrogen bonding, main chain-side chain interactions, and protecting groups on the excimer formation of bis(pyrenylalanine) peptides

Biopolymers ◽

10.1002/bip.360261103 ◽

1987 ◽

Vol 26 (11) ◽

pp. 1833-1857 ◽

Cited By ~ 3

Author(s):

R. Goedeweeck ◽

F. Ruttens ◽

F. López-Arbeloa ◽

F. C. De Schryver

Keyword(s):

Hydrogen Bonding ◽

Main Chain ◽

Protecting Groups ◽

Side Chain ◽

Excimer Formation

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The structural biology of the amyloid precursor protein APP – a complex puzzle reveals its multi-domain architecture

Biological Chemistry ◽

10.1515/hsz-2013-0280 ◽

2014 ◽

Vol 395 (5) ◽

pp. 485-498 ◽

Cited By ~ 17

Author(s):

Ina Coburger ◽

Sandra Hoefgen ◽

Manuel E. Than

Keyword(s):

Amyloid Precursor Protein ◽

Neuronal Development ◽

Transmembrane Protein ◽

Transmembrane Helix ◽

Domain Architecture ◽

Three Dimensional ◽

Proteolytic Processing ◽

Precursor Protein ◽

Type I ◽

Independent Functions

Abstract The amyloid precursor protein (APP) and its processing are widely believed to be central for the etiology of Alzheimer’s disease (AD) and appear essential for neuronal development and cell homeostasis in mammals. Many studies show the proteolysis of APP by the proteases α-, β- and γ-secretase, functional aspects of the protein and the structure of individual domains. It is, however, largely unclear and currently also widely debated of how the structures of individual domains and their interactions determine the observed functionalities of APP and how they are arranged within the three-dimensional architecture of the entire protein. Further unanswered questions relate to the physiologic function of APP, the regulation of its proteolytic processing and the structural and functional effect of its cellular trafficking and processing. In this review, we summarize our current understanding of the structure-function-relationship of the multi-domain protein APP. This type-I transmembrane protein consists of the two folded E1 and E2 segments that are connected to one another and to the single transmembrane helix by flexible segments and likely fulfills several independent functions.

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Memapsin 2, a drug target for Alzheimer's disease

Biochemical Society Symposium ◽

10.1042/bss0700213 ◽

2003 ◽

Vol 70 ◽

pp. 213-220 ◽

Cited By ~ 1

Author(s):

Gerald Koelsch ◽

Robert T. Turner ◽

Lin Hong ◽

Arun K. Ghosh ◽

Jordan Tang

Keyword(s):

Crystal Structure ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transition State ◽

Amyloid Precursor Protein ◽

Therapeutic Target ◽

Drug Target ◽

Aspartic Protease ◽

Precursor Protein ◽

Memapsin 2

Mempasin 2, a ϐ-secretase, is the membrane-anchored aspartic protease that initiates the cleavage of amyloid precursor protein leading to the production of ϐ-amyloid and the onset of Alzheimer's disease. Thus memapsin 2 is a major therapeutic target for the development of inhibitor drugs for the disease. Many biochemical tools, such as the specificity and crystal structure, have been established and have led to the design of potent and relatively small transition-state inhibitors. Although developing a clinically viable mempasin 2 inhibitor remains challenging, progress to date renders hope that memapsin 2 inhibitors may ultimately be useful for therapeutic reduction of ϐ-amyloid.

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