Proteins journey towards science and technology- Human Protein Atlas(HPA)

President Bill Clinton declared at the White House the first sequence of the entire human genome, and an arguably larger and more ambitious undertaking was being launched in Sweden. The Human Protein Atlas (HPA) vowed, through an open-access database, to catalog every protein in the human body, making the information fully free. Twenty years on, thanks to hard work, emerging technology, and the commitment of hundreds of researchers, the HPA has made tremendous strides.

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In most genes, the information needed for creating functional molecules called proteins is contained. (Other molecules that help the cell assemble proteins are formed by a few genes.) Within each cell, the path from gene to protein is complex and tightly regulated. It is made up of two main steps: transcription and translation. Transcription and translation, together, are referred to as gene expression.

The basic substrate for learning and memory is proteins. Proteins, however, are extremely short-lived molecules that need to be replenished every few days, while memories can last a lifetime. For more than 85 billion neurons in the brain, this presents a major logistical challenge: billions of proteins need to be continuously generated, shipped, handled, and placed at the right position in the cell.

However, a more complex dendritic arbor also increases the difficulty of the logistical task of supplying proteins to each part of the neuron. A more complex dendritic arbor, however, also raises the complexity of the logistic task of supplying each part of the neuron with proteins.

Each protein has a normal distance that it can cover while diffusing, which is the duration of its diffusion. The higher this value is, the more distal dendrites can enter proteins. If a dendritic branch has a wide radius, more proteins can be carried by it. To supply all synapses, the combination of two factors, the width (or ‘radii’) of dendrites and how far proteins may travel, defines the number of proteins a neuron requires to generate.  found that a neuron can reduce the total protein count and thus the cost of protein synthesis by many orders of magnitude by optimizing dendritic radii.  neuronal dendritic morphologies play a key role in shaping neuronal function in dendritic morphology and represent optimization strategies and constraints imposed by protein trafficking.

A widely discussed topic is whether technology drives biology or whether biology drives the creation of new technologies. It has been shown that because the interplay of biology and technology development is complex, there is no straightforward response.

The rapid development of mass spectrometric technologies applied to protein science has catalyzed completely new experimental methods and, resulting in the field of proteomics, opened up new types of biological questions for experimentation. There are many benefits of this technique of proteome browsing. First, for the unequivocal identification and quantification of each protein, one peptide is necessary. The number of peptides that need to be analyzed to classify and measure each gene’s product thus exceeds the number of genes in a genome. Second, data analysis becomes trivial because by correlating the acquired data with a look-up table, rather than by de novo sequencing, each protein is classified and quantified. Third, the procedure between laboratories is easily standardized. Fourth, it specifies the absolute quantity of each protein, making data sets easily comparable. Fifth, it is possible to selectively interrogate any subset of proteins, such as proteins found in organelles, subcellular fractions, or differentiated cells. Sixth, splice isoforms, proteins that are differentially modified or processed, can be completely quantified, provided that suitable reference peptides can be synthesized.

Each cell expresses only a fraction of its genes or turns them on. The remainder of the genes has been repressed or turned off. Gene control is defined as the mechanism of turning genes on and off. Regulation of genes is a major part of normal development. During growth, genes are switched on and off in various patterns to make a brain cell look and behave differently from a liver cell or a muscle cell. Gene regulation also enables cells to respond to changes in their environments quickly. Although we understand that gene regulation is important for life, this complicated mechanism is not yet completely understood.

  • Proteins catalyze, help and control biochemical processes, much like tiny machines. Proteins also carry messages between cells, help to store and transport metabolites, provide cellular architecture with structure, and protect the gates of cells. Knowing how they work has important consequences for both science in biology and the production of drugs.
  • Their protein shapes lie at the core of all these varied functions. To serve a function, each protein is custom-built. For instance, with little pockets, hemoglobin is globular in shape. These pockets are saturated with oxygen as blood passes past the lungs, and that’s how oxygen is delivered to other parts of the body.
  • As globules or rods or helices, proteins are not synthesized. They are born as single chains called amino acids with smaller units.
  • “We can predict the genes and hence protein sequences now that we have genome sequence data available for several different species.”

But we need to figure out its structure to be able to recognize the protein’s function or to target it in a useful way.

  • The underlying mathematics is incredibly difficult. A protein with 101 amino acids will have 100 connections linking the different units together, so there will be 5 × 1047  potential ways of organizing the atoms of the proteins in space altogether.
  • If all the possible structures had to be sampled by a classical computer with sufficient computational power to evaluate the correct one, it would need about 30 years.
  • A graphical technique that visualizes these possibilities for faster decision-making is the Ramachandran plot.
  • DeepMind’s AlphaFold carries out a certain kind of leap in the modern history of structural biology, as groundbreaking as Ramachandran’s work was. In 2018, in the Crucial Assessment of Protein-Structure Prediction (CASP) challenge, AlphaFold demonstrated 80% accuracy in predicting protein structures. CASP is an organization that performs community-wide studies to assess the ability of new software to correctly predict folded protein structures.
  • The Oscars of the protein-folding universe are essentially these experiments. The first one took place in 1994 and has been held every two years since then, with hundreds of teams participating.

The fact that we each have a molecular self is one element of human life that we know to be universal. In this world, every human being consists of organs, tissues, cells, and molecular machinery that forms our identity as well as our human experience. Although our lives are beautifully special, via this molecular self, we all live through them. Biologically, it connects us to those before us, those who follow us, as well as to other species with which we share our world.

Throughout the history of medicine, to grasp the foundations of human physiology and, in turn, pathophysiology, we have attempted to describe and examine the molecular self. There are many applications of this knowledge that transcend biology and loop around the topic of what it means to be a human. It improves our ability to avoid it or even cure it in the sense of human disease.

“We can predict the genes and hence protein sequences now that we have genome sequence data available for several different species.”

References:

https://www.sciencedirect.com/science/article/pii/S1044030503002897

https://science.thewire.in/the-sciences/deepmind-alphafold-protein-folding-machine-folding-dispute-casp14-microscopy-diffraction/

https://www.technologynetworks.com/proteomics/articles/the-journey-to-mapping-the-human-proteome-343448

https://medlineplus.gov/genetics/understanding/howgeneswork/makingprotein/

Early advances in DNA understanding were foundational for protein overexpression.

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