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The 70-kDa heat shock proteins (Hsp70) are chaperones with central roles in processes that involve polypeptide remodeling events. Hsp70 proteins consist of two major functional domains: an N-terminal nucleotide binding domain (NBD) with ATPase activity, and a C-terminal substrate binding domain (SBD). We present the first crystal structures of four human Hsp70 isoforms, those of the NBDs of HSPA1L
The PARP-3 protein is closely related to the PARP-1 and PARP-2 proteins, which are involved in DNA repair and genome maintenance. Here, we characterized the biochemical properties of human PARP-3. PARP-3 is able to ADP-ribosylate itself as well as histone H1, a previously unknown substrate for PARP-3. PARP-3 is not activated upon binding to DNA and is a mono-ADP-ribosylase, in contrast to PARP-1 a
Paraplegin is an m-AAA protease of the mitochondrial inner membrane that is linked to hereditary spastic paraplegias. The gene encodes an FtsH-homology protease domain in tandem with an AAA+ homology ATPase domain. The protein is believed to form a hexamer that uses ATPase-driven conformational changes in its AAA-domain to deliver substrate peptides to its protease domain. We present the crystal s
Summary Successful malaria transmission from the mosquito vector to the mammalian host depends crucially on active sporozoite motility. Sporozoite locomotion and host cell invasion are driven by the parasite's own actin/myosin motor. A unique feature of this motor machinery is the presence of very short subpellicular actin filaments. Therefore, F-actin stabilizing proteins likely play a central ro
Poly(ADP-ribose) polymerases (PARPs) activate DNA repair mechanisms upon stress- and cytotoxin-induced DNA damage, and inhibition of PARP activity is a lead in cancer drug therapy. We present a structural and functional analysis of the PARP domain of human PARP-3 in complex with several inhibitors. Of these, KU0058948 is the strongest inhibitor of PARP-3 activity. The presented crystal structures
DEXD/H-box RNA helicases couple ATP hydrolysis to RNA remodeling by an unknown mechanism. We used x-ray crystallography and biochemical analysis of the human DEXD/H-box protein DDX19 to investigate its regulatory mechanism. The crystal structures of DDX19, in its RNA-bound prehydrolysis and free posthydrolysis state, reveal an alpha-helix that inserts between the conserved domains of the free prot
Profilins are key regulators of actin dynamics. They sequester actin monomers, forming a pool for rapid polymer formation stimulated by proteins such as formins. Apicomplexan parasites utilize a highly specialized microfilament system for motility and host cell invasion. Their genomes encode only a small number of divergent actin regulators. We present the first crystal structure of an apicomplexa
Iba2 is a homolog of ionized calcium-binding adapter molecule 1 (Iba1), a 17-kDa protein that binds and cross-links filamentous actin (F-actin) and localizes to membrane ruffles and phagocytic cups. Here, we present the crystal structure of human Iba2 and its homodimerization properties, F-actin cross-linking activity, cellular localization and recruitment upon bacterial invasion in comparison wit
Spinophilin, a neuronal scaffolding protein, is essential for synaptic transmission, and functions to target protein phosphatase-1 to distinct subcellular locations in dendritic spines. It is vital for the regulation of dendritic spine formation and motility, and functions by regulating glutamatergic receptors and binding to filamentous actin. To investigate its role in regulating actin cytoskelet
Inosine triphosphatase (ITPA) is a ubiquitous key regulator of cellular non-canonical nucleotide levels. It breaks down inosine and xanthine nucleotides generated by deamination of purine bases. Its enzymatic action prevents accumulation of ITP and reduces the risk of incorporation of potentially mutagenic inosine nucleotides into nucleic acids. Here we describe the crystal structure of human ITPA
10-Formyltetrahydrofolate dehydrogenase is a ubiquitously expressed enzyme in the human body. It catalyses the formation of tetrahydrofolate and carbon dioxide from 10-formyltetrahydrofolate, thereby playing an important role in the human metabolism of one-carbon units. It is a two-domain protein in which the N-terminal domain hydrolyses 10-formyltetrahydrofolate into formate and tetrahydrofolate.
Efficient and rapid host cell invasion is a prerequisite for an intracellular parasitic life style. Pathogens typically induce receptor-mediated endocytosis and hijack the force-transducing system of a host cell to gain access to a replication-competent niche. In striking contrast, apicomplexan parasites such as Plasmodium, the causative agent of malaria, and the human and animal pathogens Toxopla
Cytidine triphosphate synthetase (CTPS) is a key enzyme in nucleic acid and phospholipid biosynthesis and its activity is increased in certain human cancers, making it a promising drug target. The crystal structure of the synthetase domain of human CTPS, which represents the first structure of a CTPS from an eukaryote, has been determined. The structure is homotetrameric and each active site is fo
Apicomplexan parasites such as Plasmodium and Toxoplasma display actomyosin-dependent motility in the absence of readily detectable actin polymers. Three recent studies indicate that parasite actin polymers, either harvested from parasites or formed from purified recombinant proteins, are exceptionally short ( approximately 100 nm). We propose that parasite motility could be directed by the transi
ADF/cofilins (AC) are essential F- and G-actin binding proteins that modulate microfilament turnover. The genome of Plasmodium falciparum, the parasite causing malaria, contains two members of the AC family. Interestingly, P. falciparum ADF1 lacks the F-actin binding residues of the AC consensus. Reverse genetics in the rodent malaria model system suggest that ADF1 performs vital functions during
Plasmodium falciparum, the etiologic agent of malaria, is a facultative intracellular parasite of the phylum Apicomplexa. A limited turnover of microfilaments takes place beneath the parasite plasma membrane, but the cytoplasm of apicomplexans is virtually devoid of F-actin. We produced Plasmodium actin in yeast. Purified recombinant Plasmodium actin polymerized inefficiently unless both gelsolin
In actin from many species H73 is methylated, but the function of this rare post-translational modification is unknown. Although not within bonding distance, it is located close to the gamma-phosphate of the actin-bound ATP. In most crystal structures of actin, the delta1-nitrogen of the methylated H73 forms a hydrogen bond with the carbonyl of G158. This hydrogen bond spans the gap separating sub
The SMC/Rad50/RecN proteins are universal DNA‐associated ABC‐type ATPases with crucial functions in genome maintenance. New insights into Rad50-DNA complex structure and cohesin regulation inspire a speculative look at the entire superfamily. Identification of a continuous DNA binding site across the Rad50 dimer interface (Liu et al, 2016; Seifert et al, 2016) suggests a similar site in cohesin. T
In mammals, IgA is the antibody class that is produced in largest quantities. The main producers are plasma cells located in the lamina propria at mucosal surfaces that secrete it as dimers covalently linked to the J chain. Polymeric immunoglobulin receptors (pIgRs) expressed on epithelial cells bind to dimeric IgA molecules and mediate basolateral to apical transcytosis, before IgA is released in
