Our last post described the sef4 protein, a crucial component of the mammalian inner ear. This post will introduce how it works and how we think about it.
The sef4 protein is a large, membrane-anchored protein that plays a prominent role in supplying information about the directionality of sound to the brain (among other things).
When we hear a sound, the molecules of our inner ear convert the electrical signals from our ears into chemical signals that go through the ear nerve cells and, ultimately, to our brains. If you want to understand why this is important—and why it’s essential for us as humans—it’s easy enough to think about sound waves hitting your eardrum. Those waves are transmitted through your head right into your brain, where they are processed by special cells called “frequency-sensitive neurons” (or “sensory neurons”).
These neurons process these electrical and chemical signals and, in turn, send them back down your nerves to your ears, where they convert them into sounds again.
That’s not what happens, though. The nerve cells in your inner ear don’t have receptors on them like receptors on receptors; instead, they have ion channels like ion channels on ion channels. Ion channels are voltage-gated proteins that allow ions (electrolytes) to pass through them from one side of their membrane to another. Those ions then pass through the remaining molecules inside their membrane until they reach their final destination: muscles or other organs needed for movement.
The sef4 protein has two ion channels in its cell membrane: one for potassium ions and one for sodium ions. When potassium ions enter it, it opens up and allows sodium ions to pass through, too; but when sodium comes in, it closes up so no more potassium can flow through; and when potassium comes out from being blocked because there is no more sodium coming in, potassium reopens its channel allowing more sodium to go into its cell membrane — which then allows more potassium to come out again!
The vast majority of proteins have four or five different types of ion channels on their cell membranes (there are some exceptions) — including many proteins that have only two or three different classes per molecule:
• Calcium channels (called calcium-activated)
• Golgi stacks (called Golgi organization)
• Potassium channels (called K+-activated)
2. What is the molecular geometry of sef4?
In my previous posts, I’ve been discussing the sef4 gene. The gene codes for a protein in all cells but not in the same proportions in different cells. This means that there is more sef4 in some cells than others. It has been suggested that this variation may be necessary for biological processes such as cancer and diabetes and for understanding the evolution of disease resistance.
In this post, I will discuss something else: how to determine the molecular geometry of sef4.
3. The Lewis structure of sef4.
There is a fascinating paper by several researchers at the University of Washington (and, I’m sure, elsewhere) who have used X-ray crystallography to determine the molecular structure of sef4. The paper is entitled “Structure and expression analysis of a selenocysteine–cysteine dyad: sef4” and can be read on arXiv.
I’ll let their abstract do all the talking:
“Structural information is essential for understanding the function of proteins and other biomolecules. Structure determines protein interactions, dynamics, activity, and signal transduction pathways. A wide variety of structural analyses are carried out in cells and tissues to elucidate protein functions, uncover specific interactions between different proteins (e.g., the interaction between EGFR and EGFR), or predict protein function based on structural properties (e.g., the interaction between GPR55 and GPR55).
A set of distinct structures has recently emerged from X-ray crystallography studies: primary structure determination, secondary structure determination, tertiary structure determination, or combinations thereof (1–3). Direct structure determination is fundamental for learning about a protein’s functional specificity because it allows one to deduce its tertiary structure.
In addition to primary structure determination, secondary structure determination provides insights into how a protein interacts with its substrate(s), how it couples to other proteins or cell components [cell components], or how it connects with its environment (e.g., lipids/phospholipids/cytoskeletal/RNA/DNA).
Such insights may also provide clues about potential future targets for drug design [drug targets]. Secondary structure analysis may help generate hypotheses about biological processes that can be investigated using more detailed structural information that can then be tested by functional assays (4).
Tertiary structure analysis can facilitate the prediction of the functional consequences of complex interactions among multiple proteins [functional consequence]. Finally, combination structures can provide insight into the molecular basis for biological processes when multiple interactions are involved (5).
One interesting question addressed by these diverse methods is whether particular classes of structures exist at specific levels within a given domain, such as basic residues within a polypeptide chain or overrepresented amino acids in an extensive collection [overrepresented amino acids]. We evaluated this question using X-ray crystallographic data obtained from several different.
4. The VSEPR theory and sef4.
The VSEPR theory of molecular geometry is a fundamental way of describing the structure of atoms, molecules, and other condensed matter. But despite its significance for biology and chemistry, it has rarely been applied to small molecules.
Sef4 is a small molecule (a water-insoluble gas) capable of forming various structures on the ground. In particular, it can create multilayered chains. This property is explained by the VSEPR theory, which states that atoms have four quantum-mechanical states (“valence states”), and electrons can occupy different quantum-mechanical states at once (“phonon states”).
The choice between these two types of the quantum-mechanical state depends on the spatial configuration of atoms. If they are in their ground state (neither valence nor phonon state), they are called “interacting atoms.”
If they occupy the same quantum-mechanical states as each other, then they are called “noninteracting atoms” and are said to be in an “inclusive bond” or an “isotope pair bond.”
Inclusion bonds can form three kinds of structures: double, triple, and bridging. The different designs have a low probability for some inclusion bonds but a high probability for others. To help understand these structures better, we need to use diagrams like this one:
A representation like this can help us visualize the structure at a more abstract level:
5. The bond angles of sef4.
Do you know how your friends will tell you how much fun they had on the weekend when you were “just hanging out”? They were having too much fun, and you were sitting around. When you’re sitting around doing nothing but playing video games and reading blogs, your friends will be disappointed in you because they deserve more. And that’s what we should expect of ourselves as well.
Aside from the lack of productivity, there is a lot to be said about spending time with friends: camaraderie shared experiences, and even human connection (Facebook is a fantastic tool to build that connection). A friend once told me:
Wisdom isn’t what we have learned through effort; it is what we have absorbed from others.
This quote resonates with me deeply. We absorb so many things from others (not simply their work) that we can learn so much from them (like their experiences, inspiration, and perspectives). I am sure there are other great quotes like this, but I think this one sums up my interests here better than most: wisdom isn’t what we have learned by our effort; it is what we have absorbed from others.
I am sure there are plenty of other great quotes like this, but I think this one sums up my interests here better than most:
The only way to be truly successful is to not care much about success.
6. The polarities of sef4.
The gene for sef4 is a protein that has long been known to be essential to various forms of cancer research. Until recently, however, no one could find it. That changed in 2013 when researchers finally succeeded in sequencing and mapping the gene located on chromosome 17p11.1. This mutation is a small deletion: it adds two nucleotides to the start of the gene.
It introduces two extra amino acids at the end (an alanine at position 26 and an aspartate at position 121). So it is not precisely a “molecule” but rather a “block” of DNA that sits within another molecule called the RING finger protein (RFP) (which is essential in many diseases).
Researchers have documented the RING finger’s role in mediating processes, including transcription, translation, DNA replication, and cell division. Given this activity, it is perhaps surprising that no one had previously attempted to understand how exactly this molecule gave rise to sef4 or what its structure might look like.
The sef4 system is a large, complex molecule with 41 atoms (a total of 71 possible chemical bonds) that helps cells communicate with each other. The sef4 system is a large, complex molecule with 41 bits (71 likely chemical bonds) that helps cells communicate with each other.
This is what SeqKit looks like:
Many people have been asking me how to design products or services for the SeqKit platform; I’d appreciate it if you’d take a moment to read this post on it for more background. I’ll be answering the questions below in bullet points:
・What is the molecular geometry of sef4?
・What are the functions / benefits / side effects of sef4?
・What are we trying to achieve by “embracing” SeqKit? What do we want to achieve by “embracing” SeqKit?
・How do we make it work? How do we make it work well?
These answers will hopefully help you think about what kind of product you might be building in the next few months and allow me to share some insights on how I approach product development. Instead of looking at an example project, check out our latest examples repo. You can also see some additional analyses on these topics:
- Determining Molecular Geometry (part 1)
- Determining Molecular Geometry (part 2)
- Determining Molecular Geometry (part 3)
- Determining Molecular Geometry (part 4)