Anion and cation binding in proteins

Watson, James David (2002) Anion and cation binding in proteins. PhD thesis, University of Glasgow.

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Abstract

Main-chain conformations where one amino acid is described as gammaR (or alphaR) and an adjacent one is gammaL (or alphaL) generally give rise to a structure where the three main-chain NH groups (one from each of the two residues and the one that follows) form a depression. Due to the electronegativities of the atoms involved, this depression is able to accommodate an atom with a whole or partial negative charge. The negatively charged atom, when present, is also stabilised through hydrogen bonds with the NH groups. We propose the name "nest" for this feature. The nest is a common motif with 8% of residues in an average protein being involved in one. It is also a novel motif even though the situations it occurs in are well known. The negatively charged atom, or anion, that often occupies the nest varies and may be a main chain carbonyl group such as in the paperclip (Schellman motif), it may also be a phosphate group as in the P-loop superfamily that binds ATP and GTP. Overlapping (compound) nests and adjacent (tandem) nests are often observed and encourage the binding of larger more complex anionic groups. Examples of this include the compound nest of the P-loop which has 5 successive NH groups that bind the p phosphate group of nucleotide triphosphate. The longest compound nests are found surrounding cysteine bound [2Fe2S] and [4Fe4S] iron sulphur centres, which are also anionic groups. A totally novel motif occurs where the first residue of the nest is Asp, Asn, Ser or Thr. In any of these cases the sidechain acts as the negatively charged group so that the sidechain is effectively interacting with its own main-chain NH group and the two that follow. These motifs are relatively common and are named depending on the identity of the side chain involved; where the first amino acid is Asn or As the motif is known as an Asx-nest, when it is Ser or Thr the motif is an ST-nest. These are important motifs and are found in the calcium-binding loops of EF-hand proteins. The discovery of the nest prompted an investigation into polypeptides where successive residues have main-chain phi,psi conformations of opposite hand (alternating enantiomeric main-chain dihedral angles). Through the creation of model polypeptides on computer the full range of possible conformations was examined producing a plot not unlike the Ramachandran plot. All alternating enantiomeric structures are ring-shaped or extended, and some are found to occur in proteins, the commonest approximating to the nest. Another conformation related to the nest but more extended is found in the four stretches of polypeptide that line the tetrameric K+ channel, in this case the main-chain CO groups are the important feature and bind the K+ ions in the channel. A different ring-shaped structure where the main-chain CO groups point to the centre of the ring is employed for specific Ca2+ ion binding in the annexin, phospholipase A2 and subtilisin loops, and the regularly arranged beta-roll loops of the serralysin protease family. This feature we propose calling the catgrip.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: E J Milner
Keywords: Biochemistry
Date of Award: 2002
Depositing User: Enlighten Team
Unique ID: glathesis:2002-71070
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 10:49
Last Modified: 10 May 2019 10:49
URI: http://theses.gla.ac.uk/id/eprint/71070

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