抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Macroautophagy (hereafter autophagy), or 'self-eating', is a conserved cellular pathway that controls protein and organelle degradation, and has essential roles in survival, development and homeostasis. Autophagy is also integral to human health and is involved in physiology, development, lifespan and a wide range of diseases, including cancer, neurodegeneration and microbial infection. Although research on this topic began in the late 1950s, substantial progress in the molecular study of autophagy has taken place during only the past 15 years. This review traces the key findings that led to our current molecular understanding of this complex process.

/pdf/eaten-alive-a-history-of-macroautophagy-4vi18tschy.pdf

Eaten alive: a history of macroautophagy.

Autophagy is a primarily degradative pathway that takes place in all eukaryotic cells. It is used for recycling cytoplasm to generate macromolecular building blocks and energy under stress conditions, to remove superfluous and damaged organelles to adapt to changing nutrient conditions and to maintain cellular homeostasis. In addition, autophagy plays a critical role in cytoprotection by preventing the accumulation of toxic proteins and through its action in various aspects of immunity including the elimination of invasive microbes and its participation in antigen presentation. The most prevalent form of autophagy is macroautophagy, and during this process, the cell forms a double-membrane sequestering compartment termed the phagophore, which matures into an autophagosome. Following delivery to the vacuole or lysosome, the cargo is degraded and the resulting macromolecules are released back into the cytosol for reuse. The past two decades have resulted in a tremendous increase with regard to the molecular studies of autophagy being carried out in yeast and other eukaryotes. Part of the surge in interest in this topic is due to the connection of autophagy with a wide range of human pathophysiologies including cancer, myopathies, diabetes and neurodegenerative disease. However, there are still many aspects of autophagy that remain unclear, including the process of phagophore formation, the regulatory mechanisms that control its induction and the function of most of the autophagy-related proteins. In this review, we focus on macroautophagy, briefly describing the discovery of this process in mammalian cells, discussing the current views concerning the donor membrane that forms the phagophore, and characterizing the autophagy machinery including the available structural information.

/pdf/the-machinery-of-macroautophagy-3yn7cwcpxq.pdf

The machinery of macroautophagy

Significance: Autophagy is a highly conserved eukaryotic cellular recycling process. Through the degradation of cytoplasmic organelles, proteins, and macromolecules, and the recycling of the breakdown products, autophagy plays important roles in cell survival and maintenance. Accordingly, dysfunction of this process contributes to the pathologies of many human diseases. Recent Advances: Extensive research is currently being done to better understand the process of autophagy. In this review, we describe current knowledge of the morphology, molecular mechanism, and regulation of mammalian autophagy. Critical Issues: At the mechanistic and regulatory levels, there are still many unanswered questions and points of confusion that have yet to be resolved. Future Directions: Through further research, a more complete and accurate picture of the molecular mechanism and regulation of autophagy will not only strengthen our understanding of this significant cellular process, but will aid in the development o...

/pdf/an-overview-of-autophagy-morphology-mechanism-and-regulation-4r1w1txfhw.pdf

An Overview of Autophagy: Morphology, Mechanism, and Regulation

The central role of phosphoinositide 3-kinase (PI3K) activation in tumour cell biology has prompted a sizeable effort to target PI3K and/or downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in cancer. However, emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. One exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukaemia, where a combination of cell-intrinsic and -extrinsic activities drive efficacy. Here, we review key challenges and opportunities for the clinical development of inhibitors targeting the PI3K-AKT-mTOR pathway. Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.

/pdf/pi3k-and-cancer-lessons-challenges-and-opportunities-59xpgux9c4.pdf

PI3K and cancer: lessons, challenges and opportunities

Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies.

/pdf/the-p110-delta-structure-mechanisms-for-selectivity-and-2y6stnhkcw.pdf

The p110[delta] structure: mechanisms for selectivity and potency of new PI(3)K inhibitors

Phosphoinositide 3-kinases (PI3Ks) are lipid kinases with diverse roles in health and disease. The primordial PI3K, Vps34, is present in all eukaryotes and has essential roles in autophagy, membrane trafficking, and cell signaling. We solved the crystal structure of Vps34 at 2.9 angstrom resolution, which revealed a constricted adenine-binding pocket, suggesting the reason that specific inhibitors of this class of PI3K have proven elusive. Both the phosphoinositide-binding loop and the carboxyl-terminal helix of Vps34 mediate catalysis on membranes and suppress futile adenosine triphosphatase cycles. Vps34 appears to alternate between a closed cytosolic form and an open form on the membrane. Structures of Vps34 complexes with a series of inhibitors reveal the reason that an autophagy inhibitor preferentially inhibits Vps34 and underpin the development of new potent and specific Vps34 inhibitors.

/pdf/shaping-development-of-autophagy-inhibitors-with-the-2snntorgsf.pdf

Shaping Development of Autophagy Inhibitors with the Structure of the Lipid Kinase Vps34

PI3Ks (phosphoinositide 3-kinases) have important roles in a variety of cellular activities, including survival, proliferation, growth, shape, migration and intracellular sorting. Consistent with their function in cell survival and growth, the gene for the class Iα PI3K catalytic subunit is a common site of gain-of-function mutations in cancers. Ongoing structural studies of these enzymes and the complexes they make with their regulatory subunits have helped to clarify the mechanistic basis of this role in tumour development. The broad spectrum of biological activities associated with various isotypes of class I PI3Ks has led to an intense search for isotype-specific inhibitors as tools in mammalian cell biology and for therapeutic application. Structural studies of the class I PI3Ks suggest that flexibility may be a component of the catalytic cycle of the enzymes.

https://www.mrc-lmb.cam.ac.uk/rlw/text/pdffiles/19614567.pdf

Form and flexibility in phosphoinositide 3-kinases

Corrigendum: The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors

/pdf/corrigendum-the-p110-delta-structure-mechanisms-for-35ipvd8xnz.pdf

Corrigendum: The p110[delta] structure: mechanisms for selectivity and potency of new PI(3)K inhibitors

Vps34 is the ancestral phosphatidylinositol 3-kinase (PtdIns3K) isoform and is essential for endosomal trafficking of proteins to the vacuole/lysosome, autophagy and phagocytosis. Vps34-containing complexes associate with specific cellular compartments to produce PtdIns(3)P. Understanding the roles of Vps34 has been hampered by the lack of potent, specific inhibitors. To boost development of Vps34 inhibitors, we determined the crystal structures of Vps34 alone and in complexes with multitargeted PtdIns3K inhibitors. These structures provided a first glimpse into the uniquely constricted ATP-binding site of Vps34 and enabled us to model Vps34 regulation. We showed that the substrate-binding "activation" loop and the flexibly attached amphipathic C-terminal helix are crucial for catalysis on membranes. The C-terminal helix also suppresses ATP hydrolysis in the absence of membranes. We propose that membrane binding shifts the C-terminal helix to orient the enzyme for catalysis, and the Vps15 regulatory subun...

Simon Miller

Papers

The p110[delta] structure: mechanisms for selectivity and potency of new PI(3)K inhibitors

Shaping Development of Autophagy Inhibitors with the Structure of the Lipid Kinase Vps34

Form and flexibility in phosphoinositide 3-kinases

Corrigendum: The p110[delta] structure: mechanisms for selectivity and potency of new PI(3)K inhibitors

Finding a fitting shoe for Cinderella