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The microtubule-associated protein (MAP)/microtubule affinity regulating kinase (MARK)/Par-1 phosphorylates microtubule-associated proteins tau, MAP2, and MAP4 and is involved in the regulation of microtubule-based transport. Par-1, a homologue of MARK in Drosophila and Caenorhabditis elegans, is essential for the development of embryonic polarity. Four isoforms of MARK are found in humans. Recently, we reported the crystal structure of the catalytic and ubiquitin-associated domains of MARK2, an isoform enriched in brain (Panneerselvam, S., Marx, A., Mandelkow, E.-M., and Mandelkow, E. (2006) Structure 14, 173-183). It showed that the ubiquitin-associated domain (UBA) domain has an unusual fold and binds to the N-terminal lobe of the catalytic domain. This is at variance with a previous low resolution structure derived from small angle solution scattering (Jaleel, M., Villa, F., Deak, M., Toth, R., Prescott, A. R., Van Aalten, D. M., and Alessi, D. R. (2006) Biochem. J. 394, 545-555), which predicts binding of the UBA domain to the larger, C-terminal lobe. Here we report the crystal structure of the catalytic and UBA domain of another isoform, MARK1. Although the crystal packing of the two isoforms are unrelated, the overall conformations of the molecules are similar. Notably, the UBA domain has the same unusual conformation as in MARK2, and it binds at the same site. Remarkable differences occur in the catalytic domain at helix C, the catalytic loop, and the activation segment.

The Ser/Thr kinase MARK2 phosphorylates tau protein at sites that cause detachment from microtubules in Alzheimer neurofibrillary degeneration. Homologs of MARK2 include Par-1 in C. elegans and Drosophila, which generates embryonic polarity. We report the X-ray structure of the catalytic and ubiquitin-associated domains (UBA) of human MARK2. The activity was altered by mutations in the ATP binding site and/or activation loop. The catalytic domain shows the small and large lobes typical of kinases. The substrate cleft is in an inactive, open conformation in the inactivated and the wild-type structure. The UBA domain is attached via a taut linker to the large lobe of the kinase domain and leans against a hydrophobic patch on the small lobe. The UBA structure is unusual because the orientation of its third helix is inverted, relative to previous structures. Possible implications of the structure for the regulation of kinase activity are discussed.

Diabetes mellitus is a disease, which virtually affects all the systems in the body including the immune system. Bacterial infections are important causes of increased morbidity and mortality in diabetic patients. In the present study, we assessed the effect of molybdate on immune responses of diabetic rats. The phagocytic potency and nitroblue tetrazolium dye reduction capacity were found to be considerably lowered whereas soluble immune complex formation enhanced significantly in diabetic rats when compared with control rats. From our findings, it is suggested that dietary intake of molybdate may have a vital role in enhancing immune functions during diabetic mellitus.

This paper reports the milk protein polymorphism, the allele frequencies of variants and the possible linkages among various combinations of milk protein phenotypes in the Kangayam cattle of south India. Milk samples from 156 Kangayam cows were typed by starch gel and polyacrylamide gel electrophoresis for caseins and whey proteins, respectively. All the four milk protein components studied, alpha(s)1-casein. beta-casein, beta-lactoglobulin and alpha-lactalbumin, exhibited polymorphism with high allele frequencies of 0.9231 +/- 0.0151 for alpha(s)1-casein C, 0.9263 +/- 0.0148 for beta-casein A, 0.9135 +/- 0.0159 for beta-lactoglobulin B and a relatively high frequency of 0.6218 +/- 0.0275 for alpha-lactalbumin A. The mean heterozygosity estimated over all the four milk protein loci was 0.2420. Genetic equilibrium was observed among all the loci studied, except alpha-lactalbumin. Linkage analysis confirmed the non-independence between alpha(s)1- and beta-caseins and between caseins and alpha-lactalbumin phenotypes.

A cohort of patients with an INR >7.0 were identified prospectively and compared with a group of patients with stable anticoagulant control. During the study 15,100 INR measurements were recorded and 31 (0.2%) were >7.0. Odds ratios of patient characteristics were calculated as an estimate of relative risk for the development of a high INR. The highest risk factor was a target INR of 3.5 (OR 7.3, 95% CI 2.6-20.2). The second highest risk factor was antibiotic therapy in the 4 weeks preceding the high INR (OR 6.2, 95% CI 1.4-27.7). Bleeding was reported more frequently in the high INR group (OR 5.4, 95% CI 2.1-13.9). Five major bleeds occurred in this group compared to none in the stable group. This analysis identifies risk factors for over-anticoagulation and hence when to intensify monitoring and when to consider pre-emptive warfarin dose reductions.