The heat shock protein 70 (Hsp70) family of molecular chaperones are crucial for the survival and pathogenicity of the main agent of malaria, Plasmodium falciparum . Hsp70 is central to cellular proteostasis and some of its isoforms are essential for survival of the malaria parasite. In addition, they are also implicated in the development of antimalarial drug resistance. For these reasons, they are thought to be potential drug targets, especially in antimalarial combination therapies. However, their high sequence conservation across species presents a hurdle with respect to their selective targeting. The human genome encodes 17 Hsp70 isoforms while P. falciparum encodes for only 6 . The structural architecture of Hsp70s is typically characterized by a highly conserved N-terminal nucleotide-binding domain (NBD) and a less conserved C-terminal substrate-binding domain (SBD). The two domains are connected by a highly conserved linker. In spite of their fairly high sequence conservation, Hsp70s from various species possess unique signature motifs that appear to uniquely influence their function. In addition, their cooperation with co-chaperones further regulates their functional specificity. In the current review, bioinformatics tools were used to identify conserved and unique signature motifs in Hsp70s of P. falciparum versus their human counterparts. We discuss the common and distinctive structure-function features of these proteins. This information is important towards elucidating the prospects of selective targeting of parasite heat shock proteins as part of antimalarial design efforts.

The COVID-19 pandemic, which started around December 2019 has, at present, resulted in over 450,000 deaths globally, and approximately 1% of these deaths have been reported in Africa. Despite the high prevalence of COVID-19 risk factors, namely: hypertension, diabetes, chronic pulmonary disease, cardiovascular diseases (CVDs) such as rheumatic heart disease, compromised immunity and obesity, low case fatality rates have been recorded in many parts of Africa so far. COVID-19 severity has previously been shown to be worse in patients with CVD and hypertension. We observed the severity of COVID-19 and mortality rates in Africa, and compared outcomes with prevalence of established risk factors (hypertension and CVD). We stratified data as per the United Nations’ 5 African subregions. North African countries show a positive association between the risk factors and the mortality rates from COVID-19. However, we observed discordant patterns in the relationship between COVID-19, and either CVD or hypertension, in sub-Saharan African countries. In this paper, we also review the pathogenesis of SARS-CoV-2 infection and how it worsens CVD and postulate that the differences in modulation of the renin–angiotensin–aldosterone system (RAAS) axis which controls angiotensin-converting enzyme (ACE)/ACE2 balance may be an important determinant of COVID-19 outcomes in Africa. Electronic supplementary material The online version of this article (10.1007/s00392-020-01720-y) contains supplementary material, which is available to authorized users.

The heat shock 70 (Hsp70) family of molecular chaperones plays a central role in maintaining cellular proteostasis. Structurally, Hsp70s are composed of an N-terminal nucleotide binding domain (NBD) which exhibits ATPase activity, and a C-terminal substrate binding domain (SBD). The binding of ATP at the NBD and its subsequent hydrolysis influences the substrate binding affinity of the SBD through allostery. Similarly, peptide binding at the C-terminal SBD stimulates ATP hydrolysis by the N-terminal NBD. Interdomain communication between the NBD and SBD is facilitated by a conserved linker segment. Hsp70s form two main subgroups. Canonical Hsp70 members generally suppress protein aggregation and are also capable of refolding misfolded proteins. Hsp110 members are characterized by an extended lid segment and their function tends to be largely restricted to suppression of protein aggregation. In addition, the latter serve as nucleotide exchange factors (NEFs) of canonical Hsp70s. The linker of the Hsp110 family is less conserved compared to that of the canonical Hsp70 group. In addition, the linker plays a crucial role in defining the functional features of these two groups of Hsp70. Generally, the linker of Hsp70 is quite small and varies in size from seven to thirteen residues. Due to its small size, any sequence variation that Hsp70 exhibits in this motif has a major and unique influence on the function of the protein. Based on sequence data, we observed that canonical Hsp70s possess a linker that is distinct from similar segments present in Hsp110 proteins. In addition, Hsp110 linker motifs from various genera are distinct suggesting that their unique features regulate the flexibility with which the NBD and SBD of these proteins communicate via allostery. The Hsp70 linker modulates various structure-function features of Hsp70 such as its global conformation, affinity for peptide substrate and interaction with co-chaperones. The current review discusses how the unique features of the Hsp70 linker accounts for the functional specialization of this group of molecular chaperones.

Heat shock protein 90 (Hsp90) is essential for the development of the main malaria agent, Plasmodium falciparum. Inhibitors that target Hsp90 function are known to not only kill the parasite, but also reverse resistance of the parasite to traditional antimalarials such as chloroquine. For this reason, Hsp90 has been tagged as a promising antimalarial drug target. As a molecular chaperone, Hsp90 facilitates folding of proteins such as steroid hormone receptors and kinases implicated in cell cycle and development. Central to Hsp90 function is its regulation by several co-chaperones. Various co-chaperones interact with Hsp90 to modulate its co-operation with other molecular chaperones such as Hsp70 and to regulate its interaction with substrates. The role of Hsp90 in the development of malaria parasites continues to receive research attention, and several Hsp90 co-chaperones have been mapped out. Recently, focus has shifted to P. falciparum R2TP proteins, which are thought to couple Hsp90 to a diverse set of client proteins. R2TP proteins are generally known to form a complex with Hsp90, and this complex drives multiple cellular processes central to signal transduction and cell division. Given the central role that the R2TP complex may play, the current review highlights the structure-function features of Hsp90 relative to R2TPs of P. falciparum. Keywords Plasmodium falciparum . Heat shock protein 90 . R2TP proteins Plasmodium falciparum Hsp90Plasmodium falciparum constitutes the main agent of malaria. P. falciparum develops in cold-blooded mosquito vectors and is transmitted to warm-blooded human hosts when mosquitoes take up a human blood meal (Fig. 1). Thus, one of the main requirements for the parasite's survival is the need to adapt to physiological changes. The rapid replication of the parasites within the human host is driven by the synthesis of biomolecules such as lipids and proteins (Santiago et al. 2004;Absalon et al. 2016). As such, proteostasis is central to the * Addmore Shonhai

Peripartum cardiomyopathy (PPCM) is a condition in which heart failure and systolic dysfunction occur late in pregnancy or within months following delivery. Over the last decade, genetic advances in heritable cardiomyopathy have provided new insights into the role of genetics in PPCM. In this review, we summarise current knowledge of the genetics of PPCM and potential avenues for further research, including the role of molecular chaperone mutations in PPCM. Evidence supporting a genetic basis for PPCM has emanated from observations of familial disease, overlap with familial dilated cardiomyopathy, and sequencing studies of PPCM cohorts. Approximately 20% of PPCM patients screened for cardiomyopathy genes have an identified pathogenic mutation, with TTN truncations most commonly implicated. As a stress-associated condition, PPCM may be modulated by molecular chaperones such as heat shock proteins (Hsps). Recent studies have led to the identification of Hsp mutations in a PPCM model, suggesting that variation in these stress-response genes may contribute to PPCM pathogenesis. Although some Hsp genes have been implicated in dilated cardiomyopathy, their roles in PPCM remain to be determined. Additional areas of future investigation may include the delineation of genotype-phenotype correlations and the screening of newly-identified cardiomyopathy genes for their roles in PPCM. Nevertheless, these findings suggest that the construction of a family history may be advised in the management of PPCM and that genetic testing should be considered. A better understanding of the genetics of PPCM holds the potential to improve treatment, prognosis, and family management.