This is a review-cum-hypothesis about beta/alpha barrel (or TIM barrel) proteins, presenting a fresh set of perspectives about the structure, architecture and topology of such proteins in light of views concerning their folding through the step-wise, co-translational folding and assembly of individual beta-alpha units consisting of a beta-strand, a long loop, an alpha helix and a short loop. The paper argues that TIM barrels must fold in a step-wise fashion, and not in an all-or-none two-state folding reaction, because the very architecture of the barrel and the differential folding times of alpha helices and beta sheets preclude any two-state folding.
In this paper, we ask the following molecular recognition-related question: ‘when two proteins aggregate under the same conditions, do they homo-aggregate with likenesses of themselves, or do they hetero-aggregate, with chains sections of one protein forming intermolecular beta sheets with the chain sections of another protein?’. We take differentially fluorescently-labelled forms of two proteins that aggregate, under similar conditions, into amyloid-like microstructures (even if these are in amorphous ‘macro’ forms initially) and show that they are uniformly hetero-aggregated, to the extent that this can be resolved through confocal fluorescence microscopy examining small volumes within aggregates. Each volume examined contains about a million protein chains, and within this resolution, all sections of the aggregates show fluorescence signals derived from both chains, suggesting hetero-aggregation. Of course, it must be mentioned that this technique would probably not work with proteins that retain significant native structure while aggregating, because such proteins would very likely homo-aggregate by recognizing likenesses of chains possessing the same identity.

This paper is about our efforts to collaboratively determine the structure of a pigment made by a fungus which is an opportunistic pathogen infecting patients who are already infected by the human immunodeficiency virus. When de novo structure determination efforts failed, we used some data from spectroscopic and other techniques and some informed guesses based on the known structure of another pigment, to determine the structure of this pigment, in a partly-sound and partly-speculative exercise.

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