Bothnia dystrophy is caused by domino-like rearrangements in cellular retinaldehyde-binding protein mutant R234W

Cellular retinaldehyde-binding protein (CRALBP) is essential for mammalian vision by routing 11-cis-retinoids for the conversion of photobleached opsin molecules into photosensitive visual pigments. The arginine-to-tryptophan missense mutation in position 234 (R234W) in the human gene RLBP1 encoding CRALBP compromises visual pigment regeneration and is associated with Bothnia dystrophy. Here we report the crystal structures of both wild-type human CRALBP and of its mutant R234W as binary complexes complemented with the endogenous ligand 11-cis-retinal, at 3.0 and 1.7 A resolution, respectively. Our structural model of wild-type CRALBP locates R234 to a positively charged cleft at a distance of 15 A from the hydrophobic core sequestering 11-cis-retinal. The R234W structural model reveals burial of W234 and loss of dianion-binding interactions within the cleft with physiological implications for membrane docking. The burial of W234 is accompanied by a cascade of side-chain flips that effect the intrusion of the side-chain of I238 into the ligand-binding cavity. As consequence of the intrusion, R234W displays 5-fold increased resistance to light-induced photoisomerization relative to wild-type CRALBP, indicating tighter binding to 11-cis-retinal. Overall, our results reveal an unanticipated domino-like structural transition causing Bothnia-type retinal dystrophy by the impaired release of 11-cis-retinal from R234W.

The role of specialisation in the promotion of young football talents: A person-oriented study

This paper investigates the controversial question whether it is more effective to promote specialisation in a specific sport at the beginning of a career or whether to encourage a broad range of sports when promoting competitive sports talents in order for them to achieve a high level of performance in adulthood. The issue of promoting talents depends on human developmental processes and therefore raises developmental scientific questions. Based on recent, dynamic-interactionist concepts of development, we assume a person-oriented approach focussing on the person as a whole rather than individual features. Theoretical considerations lead to four interacting factors being summarised to form a subsystem: childhood training. The relative weights of these factors lead to patterns. By relating these to a performance criterion at the age of peak performance, particularly promising developmental patterns may be identified. One hundred fifty-nine former Swiss football talents were retrospectively interviewed about their career and the data analysed using the LICUR method. Two early career patterns were identified as having a favourable influence on adult performance. Both are characterised by an above-average amount of in-club training. One pattern also exhibits an above-average amount of informal football played outside the club, the other above-average scores for activity in other sports. Hence, comprehensive training and practice inside and outside the club form the basis for subsequent football expertise.