Although all ferredoxin-NADP+ reductases (FNRs) catalyze the same reaction. i. e. the transfer of reducing equivalents between NADP(H) and ferredoxin, they belong to two unrelated families of proteins: the plant type and the glutathione reductase type of FNRs. Aim of this review is to provide a general classification scheme for these enzymes, to be used as a framework for the comparison of their properties.Furthermore, we report on some recent findings, which significantly increased the understanding of the structure-function relationships of FNRs, i.e. the ability of adrenodoxin reductase and its homologs to catalyze the oxidation of NADP+ to its 4-oxo derivative, and the properties of plant-type FNRs from non- Subject: revision of ms ABBI-07-950Dear Editor, we would like to thank the Reviewers for their criticisms and suggestions that hopefully allowed us to improve our article. We carefully revised the manuscript according to the Reviewer's suggestions. The overall length of the paper has been significantly reduced by shortening longer chapters and by deleting three figures.The major changes in the revised version of the manuscript are as follows: Fig. 1, GR-type FNRs represent a broader group that include both the AdR-like and the ONFR-like enzymes. Thus, we prefer to maintain the distinction between the two terms (GR-type and AdR-like).2) While most of the chapters have similar lengths, the last two chapters are significantly longer than the previous six ones, creating an unpleasant imbalance in the presentation. The authors should try to either condense or split in multiple chapters the two long ones, in order to have a more armonious and balanced presentation of the topics. Large chapters ("Specific features of Plasmodium falciparum FNR" and "Ferredoxin binding and electron-transfer") were significantly shortened (by 35% and 22%, respectively). Previous very long paragraphs were broken into smaller ones.3) The work would significantly gain in strength upon adding a small summary paragraph at the end of the review article. Alternatively, the authors may consider a paragraph in which they present open questions that can now be raised and answered based upon current knowledge. A Conclusion chapter has been added. However, in order to limit the ms length, this chapter is not a summary or a list of open questions, but includes just some concluding remarks. 5) A list of abbreviations should be included. For example, what is NMN?A list of abbreviations has been added. 6) On page 4 line 15, both n and S should be defined.The definition of the parameters n and S has been given, and a reference added. 7) The authors should specify clearly which enzymes have been wrongly identified as adrenodoxin reductase-like enzymes (page 6).What we found is that some AdR-like proteins have been wrongly identified as other enzymes, and not the opposite. We think that, for the sake of brevity, it is not possible to give a comprehensive list of incorrectly identified entries within this review article. We have provide...

Spontaneous aggregation of folded and soluble native proteins in vivo is still a poorly understood process. A prototypic example is the D76N mutant of beta-2 microglobulin (β2m) that displays an aggressive aggregation propensity. Here we investigate the dynamics of β2m by X-ray crystallography, solid-state NMR, and molecular dynamics simulations to unveil the effects of the D76N mutation. Taken together, our data highlight the presence of minor disordered substates in crystalline β2m. The destabilization of the outer strands of D76N β2m accounts for the increased aggregation propensity. Furthermore, the computational modeling reveals a network of interactions with residue D76 as a keystone: this model allows predicting the stability of several point mutants. Overall, our study shows how the study of intrinsic dynamics in crystallo can provide crucial answers on protein stability and aggregation propensity. The comprehensive approach here presented may well be suited for the study of other folded amyloidogenic proteins.

Plants measure day or night lengths to coordinate specific developmental changes with a favorable season. In rice (Oryza sativa), the reproductive phase is initiated by exposure to short days when expression of HEADING DATE 3a (Hd3a) and RICE FLOWERING LOCUS T 1 (RFT1) is induced in leaves. The cognate proteins are components of the florigenic signal and move systemically through the phloem to reach the shoot apical meristem (SAM). In the SAM, they form a transcriptional activation complex with the bZIP transcription factor OsFD1 to start panicle development. Here, we show that Hd3a and RFT1 can form transcriptional activation or repression complexes also in leaves and feed back to regulate their own transcription. Activation complexes depend on OsFD1 to promote flowering. However, additional bZIPs, including Hd3a BINDING REPRESSOR FACTOR1 (HBF1) and HBF2, form repressor complexes that reduce Hd3a and RFT1 expression to delay flowering. We propose that Hd3a and RFT1 are also active locally in leaves to fine-tune photoperiodic flowering responses.

Dilated cardiomyopathy (DCM) frequently affects relatively young, economically, and socially active adults, and is an important cause of heart failure and transplantation. DCM is a complex disease and its pathological architecture encounters many genetic determinants interacting with environmental factors. The old perspective that every pathogenic gene mutation would lead to a diseased heart, is now being replaced by the novel observation that the phenotype depends not only on the penetrance-malignancy of the mutated gene-but also on epigenetics, age, toxic factors, pregnancy, and a diversity of acquired diseases. This review discusses how gene mutations will result in mutation-specific molecular alterations in the heart including increased mitochondrial oxidation (sarcomeric gene e.g. TTN), decreased calcium sensitivity (sarcomeric genes), fibrosis (e.g. LMNA and TTN), or inflammation. Therefore, getting a complete picture of the DCM patient will include genomic data, molecular assessment by preference from cardiac samples, stratification according to co-morbidities, and phenotypic description. Those data will help to better guide the heart failure and anti-arrhythmic treatment, predict response to therapy, develop novel siRNA-based gene silencing for malignant gene mutations, or intervene with mutation-specific altered gene pathways in the heart.This article is part of the Mini Review Series from the Varenna 2017 meeting of the Working Group of Myocardial Function of the European Society of Cardiology.

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