Functional and biophysical analysis of the C-terminus of the CGRP-receptor; a family B GPCR

G-protein coupled receptors (GPCRs) typically have a functionally important C-terminus which, in the largest subfamily (family A), includes a membrane-parallel eighth helix. Mutations of this region are associated with several diseases. There are few C-terminal studies on the family B GPCRs and no data supporting the existence of a similar eighth helix in this second major subfamily, which has little or no sequence homology to family A GPCRs. Here we show that the C-terminus of a family B GPCR (CLR) has a disparate region from N400 to C436 required for CGRP-mediated internalization, and a proximal region of twelve residues (from G388 to W399), in a similar position to the family A eighth helix, required for receptor localization at the cell surface. A combination of circular and linear dichroism, fluorescence and modified waterLOGSY NMR spectroscopy (SALMON) demonstrated that a peptide mimetic of this domain readily forms a membrane-parallel helix anchored to the liposome by an interfacial tryptophan residue. The study reveals two key functions held within the C-terminus of a family B GPCR and presents support for an eighth helical region with striking topological similarity to the nonhomologous family A receptor. This helix structure appears to be found in most other family B GPCRs.

Strategy paradigms for the management of quality:dealing with complexity

Quality management is dominated by rational paradigms for the measurement and management of quality, but these paradigms start to “break down”, when faced with the inherent complexity of managing quality in intensely competitive changing environments. In this article, the various theoretical strategy paradigms employed to manage quality are reviewed and the advantages and limitations of these paradigms are highlighted. A major implication of this review is that when faced with complexity, an ideological stance to any single strategy paradigm for the management of quality is ineffective. A case study is used to demonstrate the need for an integrative multi-paradigm approach to the management of quality as complexity increases.

Evolving forms of manufacturing strategy development:evidence and implications

This paper outlines, using evidence from several case studies, the use of alternative forms of manufacturing strategy processes. Our investigation shows that the manufacturing strategy development practices of manufacturers are evolving in many directions; we found several alternatives to the formal top-down planning process. Manufacturers use one or more of the following alternatives with or without the top-down manufacturing strategy process: a coherent pattern of actions; manufacturing/process improvement programs; or the pursuit of core manufacturing capabilities. It appears that the various manufacturing strategy development processes may be tied to the strategic role of manufacturing in a company. This paper offers a framework that captures the relationship between the strategic role of manufacturing and the process of manufacturing strategy development. An in-depth case from a UK company illustrates the evolving forms of manufacturing strategy development processes.