Functional consequences and structural interpretation of mutations of human choline acetyltransferase

PubMed ID: 21786365Choline acetyltransferase (ChAT; EC 2.3.1.6) catalyzes synthesis of acetylcholine from acetyl-CoA (AcCoA) and choline in cholinergic neurons. Mutations in CHAT cause potentially lethal congenital myasthenic syndromes associated with episodic apnea (ChAT-CMS). Here, we analyze the functional consequences of 12 missense and one nonsense mutations of CHAT in 11 patients. Nine of the mutations are novel. We examine expression of the recombinant missense mutants in Bosc 23 cells, determine their kinetic properties and thermal stability, and interpret the functional effects of 11 mutations in the context of the atomic structural model of human ChAT. Five mutations (p.Trp421Ser, p.Ser498Pro, p.Thr553Asn, p.Ala557Thr, and p.Ser572Trp) reduce enzyme expression to less than 50% of wild-type. Mutations with severe kinetic effects are located in the active-site tunnel (p.Met202Arg, p.Thr553Asn, and p.Ala557Thr) or adjacent to the substrate binding site (p.Ser572Trp), or exert their effect allosterically (p.Trp421Ser and p.Ile689Ser). Two mutations with milder kinetic effects (p.Val136Met and p.Ala235Thr) are also predicted to act allosterically. One mutation (p.Thr608Asn) below the nucleotide binding site of CoA enhances dissociation of AcCoA from the enzyme-substrate complex. Two mutations introducing a proline residue into an ?-helix (p.Ser498Pro and p.Ser704Pro) impair the thermal stability of ChAT. ©2011 Wiley Periodicals, Inc

Monastic governance: forgotten prospects for public institutions

To overcome agency problems, public sector reforms started to introduce businesslike incentive structures to motivate public officials. By neglecting internal behavioral incentives, however, these reforms often do not reach their stated goals. Our research analyzes the governance structure of Benedictine monasteries in order to gain new insights into solving agency problems in public institutions. A comparison is useful because members of both organizational forms, public organizations and monasteries, see themselves as responsible participants in their community and claim to serve the public good. We study monastic governance from an economic perspective. Benedictine monasteries in Baden-Württemberg, Bavaria, and German-speaking Switzerland have an average lifetime of almost 500 years, and only a quarter of them broke up because of agency problems. We argue that they were able to survive for centuries due to an appropriate governance structure, relying strongly on the intrinsic motivation of the members and internal control mechanisms. This governance approach differs in several aspects from current public sector reforms. JEL Classification: D73, G3, Z12, H83 Keywords: Public Governance, New Public Management, Public Sector Reform, Psychological Economics, Agency Problems, Monasteries, Benedictine Orde

The Relationship Between Labor Market Structure and Clergy Compensation in Protestant Denominations

Labor markets, Economic analysis of religion, Economic justice, I30, J31, J42, L14, L22, Z12,