Showing papers by "Lutz Schmitt published in 2000"

Kinetics of Peptide Binding to the Class II MHC Protein I−Ek†

Abstract: Class II MHC glycoproteins bind short (7-25 amino acid) peptides in an extended type II polyproline-like conformation and present them for immune recognition. Because empty MHC is unstable, measurement of the rate of the second-order reaction between peptide and MHC is challenging. In this report, we use dissociation of a pre-bound peptide to generate the active, peptide-receptive form of the empty class II MHC molecule I-Ek. This allows us to measure directly the rate of reaction between active, empty I-Ek and a set of peptides that vary in structure. We find that all peptides studied, despite having highly variable dissociation rates, bind with similar association rate constants. Thus, the rate-limiting step in peptide binding is minimally sensitive to peptide side-chain structure. An interesting complication to this simple model is that a single peptide can sometimes bind to I-Ek in two kinetically distinguishable conformations, with the stable peptide-MHC complex isomer forming much more slowly than the less-stable one. This demonstrates that an additional free-energy barrier limits the formation of certain specific MHC-peptide complex conformations.

Affinity, specificity, diversity: a challenge for the ABC transporter TAP in cellular immunity.

Abstract: The immune system is a perfect piece of machinery that serves only one purpose: to protect and defend our organism. The fact that we are still alive, although surrounded by a hostile environment, demonstrates impressively how well the immune system performs this task. Over the past decades our knowledge about the functions and components of the immune system has increased exponentially. Especially for the humoral immune system and its key players, the antibodies, a detailed knowledge about structure and function as well as regulation and communication between the individual components exists. In case of the cellular immune system that knowledge is not as profound as for the humoral counterpart. In this article we do not intend to give a complete overview about both branches of the immune system. Rather, we want to focus on an essential protein of the cellular immune system, the transporter associated with antigen processing (TAP). This transmembrane protein complex displays unique properties with respect to recognition and translocation of a vast spectrum of antigenic peptides. Its important role within the major histocompatibility complex (MHC) class I mediated immune response has been utilized by some viruses which target TAP to hide and escape from a deadly attack by the immune system. Here we summarize the existing data and analyze structural and mechanistic aspects of recognition and transport by which this transporter performs its task.