Molecular Structure Of Genes Pdf Download: Discover the Role of Genes in Heredity and Mutation

A centralized page providing access and links to resources developed by the Structure Group of the NCBI Computational Biology Branch (CBB). These resources cover databases and tools to help in the study of macromolecular structures, conserved domains and protein classification, small molecules and their biological activity, and biological pathways and systems.

A collection of sequence alignments and profiles representing protein domains conserved in molecular evolution. It also includes alignments of the domains to known 3-dimensional protein structures in the MMDB database.

Molecular Structure Of Genes Pdf Download

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PUG provides access to PubChem services via a programmatic interface. PUG allows users to download data, initiate chemical structure searches, standardize chemical structures and interact with the E-utilities. PUG can be accessed using either standard URLs or via SOAP.

With its basic role in the turnover of proteins and organelles, autophagy has multiple physiological and pathophysiological functions. During tumorigenesis, autophagy plays an important role. In this review, the molecular basis of autophagy and its roles in cancer are summarized.

Although autophagic structures by electron microscopy examination were firstly reported by Christian de Duve under 60 years ago, the molecular mechanism of autophagy regulation remained mostly unknown until discovery of yeast Atg genes in the 1990s, which greatly promoted the mechanistic understanding of autophagy and clarified the fact that autophagy plays important roles in various biological processes [46,47,48,49]. Functionally, multiple autophagy-related proteins regulate and control various stages of the autophagy formation, including initiation of autophagy, nucleation of the multiple Atg proteins at PAS, elongation of the isolation membrane, and maturation of autophagosome, trafficking of mature autophagosomes, autophagosome docking and fusion with lysosomal membranes, and degradation of intra-autophagosomal contents in autophagolyosome by a hierarchical manner [17, 31].

Regulation of autophagy can be used as effective interventional strategies for cancer prevention and therapy by preventing cancer development, limiting tumor progression, and increasing the efficiency of cancer treatment. On the one hand, autophagy, as one type of programmed cell death, is ubiquitous in various cancer, functions as a tumor suppressor pathway, facilitates the degradation of oncogenic molecules, and finally prevents development of cancers. So defective or inadequate levels of autophagy can lead to cancer. Investigations showed that all chemotherapeutic agents and radiotherapies induce cancer metabolic stress and concomitant inhibition of autophagy, indicating that the autophagy regulation represents a significant direction in the development of anticancer therapies. On the other hand, autophagy, the type II programmed cell death, is involved in several signaling pathways during tumorigenesis via coordinating with apoptosis, the type I programmed cell death. Under stress conditions such as hypoxic or low-nutrition environments autophagy facilitates the survival of tumor cells, and at same time, apoptosis prevents the survival of cancer cells, indicating that autophagy and apoptosis, as two catabolic pathways, are essential for organismal homeostasis and tumor microenvironment. Investigations have now shown that autophagy and apoptosis are interconnected and coordinated by several molecular nodes of crosstalk, such as interaction of Beclin1 with Bcl-2, UVRAG with Bif-1, and ATG12 with the Mcl-1, etc.

Medicine now exists in a cellular and molecular era, where experimental biologists and clinicians seek to understand and modify cell behaviour through targeted molecular approaches. To generate a molecular understanding of cells, the cells can be assessed in a variety of ways, for example through analyses of genomic DNA sequences, chromatin structure, messenger RNA (mRNA) sequences, non-protein-coding RNA, protein expression, protein modifications and metabolites. Given that the absolute quantity of any of these molecules is very small in a single living cell, for practical reasons many of these molecules have been assessed in ensembles of thousands to billions of cells. This approach has yielded much useful molecular information, for example in genome-wide association studies (GWASs), where genomic DNA assessments have identified single-nucleotide polymorphisms (SNPs) in the genomes of individual humans that have been associated with particular biological traits and disease susceptibilities.

In many respects, mitochondria resemble α-proteobacteria, from which they are thought to have originated by endocytosis some 1.6 billion years ago. The most striking evidence of this evolutionary relationship is the close homology of bacterial and mitochondrial respiratory chain complexes. Mitochondria have their own genetic system, which uses a distinct DNA code that differs both from that of their bacterial ancestors and their eukaryotic hosts [5]. They have their own protein translation machinery, complete with ribosomes, tRNAs and associated protein factors that more or less resemble those of their bacterial ancestors. Very recently, the first high-resolution structure of a mitochondrial ribosome, determined by single-particle electron cryomicroscopy (cryo-EM), has revealed a fascinating patchwork of similarities to and differences from bacterial ribosomes [6]. Nevertheless, mitochondria make surprisingly little use of their specialized protein production machinery. In the course of evolution they have transferred up to 99 % of their genes to the nucleus. Today, the vast majority of mitochondrial proteins are produced in the cytoplasm and imported into the organelle by an elaborate set of protein translocases [7]. In humans, only 13 mitochondrial proteins are organelle-encoded, all of them central, hydrophobic subunits of respiratory chain complexes or of the ATP synthase.

Mitochondria can be seen in the light microscope, but their detailed internal structure is only revealed by electron microscopy. In the 1990s, the structure of mitochondria was investigated by electron tomography of thin plastic sections [14]. While this yielded striking three-dimensional (3D) images of their internal membrane system, molecular detail was lost due to chemical fixation, dehydration and heavy-metal staining. Cryo-EM of unfixed, unstained organelles is now revealing the architecture of mitochondrial membranes and their macromolecular components at increasing levels of detail. Single-particle cryo-EM of isolated, detergent-solubilized membrane protein complexes reaches near-atomic resolution [15, 16]. Electron cryo-tomography (cryo-ET) of intact isolated mitochondria or mitochondrial membranes is resolving their macromolecular components in situ [17], and averaging of tomographic volumes can attain sub-nanometer resolution [18].

The inner and outer membranes of mitochondria define three compartments within the organelle, each with its distinct role and corresponding protein components. The innermost compartment, surrounded by the inner membrane, is the mitochondrial matrix. It is the equivalent of the bacterial cytoplasm, from which it is distinguished by a pH of 7.9 to 8 [20], similar to that in the chloroplast stroma. The high pH of the mitochondrial matrix creates the trans-membrane electrochemical gradient that drives ATP synthesis (see below). The mitochondrial matrix is the site of organellar DNA replication, transcription, protein biosynthesis and numerous enzymatic reactions. Mitochondrial DNA is compacted by the mitochondrial transcription factor TFAM into supramolecular assemblies called nucleoids, of which there are about 1000 per cell [21]. Nucleoids are roughly spherical, with a diameter of 100 nm, each containing one copy of mitochondrial DNA [22]. Mitochondrial ribosomes are membrane-attached, as their only products (in human cells) are hydrophobic membrane protein subunits, which integrate directly into the inner membrane upon translation. A 25 Å resolution structure of the membrane-bound mitochondrial ribosome has recently been obtained by cryo-ET and sub-tomogram averaging [23].

The respiratory chain complexes have been studied in great detail for decades. High-resolution X-ray structures are available for mitochondrial complex III [44] and IV [45]. At a molecular mass of 1 megadalton (MDa), mitochondrial complex I is far larger and has more subunits than complexes III and IV put together. As yet there is no X-ray structure of the mammalian complex, but very recently a 3.6 Å X-ray structure of complex I from the obligate aerobic yeast Yarrowia lipolytica has been obtained [46]. Comparison to the high-resolution X-ray structure of the 550 kDa complex I from the thermophilic bacterium Thermus thermophilus [47] indicates that the 14 conserved core subunits have essentially the same structure in both, including three proton antiporter modules in the membrane and eight iron-sulfur clusters in the matrix arm. The mitochondrial complex has about three times as many protein subunits as its bacterial ancestor. Most functions of the extra subunits are unknown, but many of them are likely to work in assembly or the regulation of complex I function. Features that are conserved from bacteria to mitochondria include a long horizontal α-helix on the matrix side that may stabilize the membrane domain. The recent 5 Å single-particle cryo-EM structure of bovine heart complex I (Fig. 6) has resolved the proton-translocating modules, iron-sulfur clusters and long horizontal helix, and 14 of the 31 supernumerary mammalian complex I subunits have been identified [48]. However, the way in which electron transfer from NADH to ubiquinone in complex I is coupled to proton translocation is still unknown, and much else remains to be discovered.

Concerning macromolecular structure and function, we do not yet understand the precise role of the highly conserved feature of ATP synthase dimers and dimer rows in the cristae and the interplay between the MICOS complex and the dimer rows in cristae formation. Are there other factors involved in determining crista size and shape? 2ff7e9595c