Lipid‐induced conformational changes in glucagon, secretin, and vasoactive intestinal peptide

Abstract

SynopsisThe CD of glucagon, secretin, and vasoactive intestinal peptide has been studied as a function of temperature in water and in aqueous solutions of dodecyl sulfate, phosphatidyl glycerol, and L-a-phosphatidic acid (dipalmitoyl). The anionic detergent and lipids induce helix formation in all three peptides, with the amount of induced helical content increasing in the order glucagon < secretin < vasoactive intestinal peptide. These observations are subject to quantitative rationalization using a matrix formulation for the configuration partition function. In this formulation the major conformational consequences of the interaction with anionic lipids or detergents is an increase in the probability for helix formation by arginyl, histidyl, and lysyl residues. The region in which helix formation is maximal is found to he a t amino acid residues 13-20 in all three peptides. Other studies have implicated this portion of the polypeptide chain in receptor binding. Thus, the helical segment induced by interaction with anionic lipids may play an important physiological role.The gastrointestinal hormones glucagon,' s e~r e t i n ,~.~ and vasoactive intestinal p e~t i d e * ?~ have amino acid sequences ( Fig. 1) that suggest they are derived from a common ancestor.6-s Similarities are not confined to their covalent structures. While each peptide displays certain unique a c t i~n s ,~-l~ they also have many biological activities in common.12 One area of great current interest is their potential involvement as neurotransmitters.None of these peptides is highly ordered in a dilute aqueous solution. The present study is also of interest from a purely theoretical point of view. While the amino acid sequences of glucagon, secretin, and vasoactive intestinal peptide exhibit extensive homology, those differences which do occur are responsible for the prediction that these peptides should show significantly different helical content in the presence of anionic lipids. If the configuration partition function is formulated in the manner used earlier for other peptides and proteins,l3-I6 the helical content in the presence of an anionic lipid is predicted to increase in the order glucagon < secretin < vasoactive intestinal peptide. Thus, the behavior of these peptides provides a sensitive test for the validity of assumptions used in the treatment of processes by which anionic lipids induce order in polypeptides and proteins. Glucagon H S O G T -F T S D EXPERIMENTALMaterials were purchased from the following sources: vasoactive intestinal peptide from Vega Biochemicals; secretin from United States Biochemical Corporation; glucagon, L-cr-phosphatidic acid (dipalmitoyl), and L-a-lysophosphatidylcholine (palmitoyl) from Sigma Chemical Company; phosphatidyl glycerol from Calbiochem; and sodium dodecyl sulfate from Matheson, Coleman, and Bell Manufacturing Chemists.CD measurements were conducted on protein solutions prepared by dilution of a stock solution with distilled deionized water. The pH was measured with a Beckman 3500 pH meter...

Structural homology of corticotropin-releasing factor, sauvagine, and urotensin I: circular dichroism and prediction studies.

“…It has been hypothesized that they are crucial to the function of binding to lipids and cell membranes (24)(25)(26). Studies of synthetic analogs containing amphiphilic portions of apolipoproteins (27,28), mellitin (25), and (3-endorphin (26) der in H20 have significant helical structure in the presence of lipids, in agreement with their predicted helical potential (30,31). The functional importance of the amphiphilic helices is pinpointed by the low activity of CRF10-41, which lacks only the first three residues of this structural unit (4).…”

Cleavage specificity of a proteolytic antibody light chain and effects of the heavy chain variable domain 1 1Edited by A.R.Fersht

“…Thus, the V H domain must also exert a bene®cial effect on stabilization of the transition state of VIP, even though its interactions with VIP appear to be limited to a subsite remote from the reaction center. The possible explanations for this novel behavior are: (1) ground state destabilizing effects at the reaction center in VIP, as opposed to overall stabilization of the peptide occurring upon F v binding, could lead to an improved catalytic rate constant and kinetic ef®-ciency, as is theoretically possible in catalysts containing distinct chemically reactive and ground state binding subsites (Menger, 1992); or (2) in view of the large contact area available within antibody active sites and the¯exibility of small polypeptide substrates like VIP (Robinson et al, 1982), the V H domain may stabilize transition statespeci®c subsites in VIP remote from the tetrahedral carbon at the scissile bond. This hypothesis is supported by computer models of VIP, in which conversion of the trigonal carbon at the Lys20 ± Lys21 scissile bond to a tetrahedral state produced spatial movements of the backbone and amino acid sidechains distant from the scissile bond, raising the possibility of formation of new subsites in the transition state (Paul, 1996).…”

Modulation of Glucagon-like Peptide-1 (GLP-1) Potency by Endocannabinoid-like Lipids Represents a Novel Mode of Regulating GLP-1 Receptor Signaling

“…Putting these findings together, it is most likely that binding of OEA to GLP-1 may induce a conformational change of the peptide and is accompanied with an enhancement in potency. This proposed model is evocative of a scenario in which peptide ligands for class B GPCRs can be induced to undergo a conformational change in the presence of lipids (38) or upon interaction with their cognate receptors (39).…”