What Is STIM1 and What Does This Protein Do?

Stromal Interaction Molecule 1 (STIM1) is a protein that functions as a cellular sensor. Found in a wide variety of human cells, it plays a part in monitoring and responding to the cell’s internal environment. STIM1 is specifically attuned to fluctuations in calcium levels, an element in cellular communication. The discovery of STIM1 provided insight into how cells manage internal signaling pathways to maintain stable conditions.

Unveiling STIM1: A Key Cellular Sensor

STIM1 was first identified in stromal cells, a type of connective tissue cell, which gave the protein its name. It is a single-pass transmembrane protein, meaning a segment of it crosses an internal cellular membrane one time. STIM1 primarily resides in the membrane of the endoplasmic reticulum (ER), an organelle that serves as the cell’s main calcium reservoir.

The structure of STIM1 is related to its role as a sensor. It consists of an N-terminal portion inside the endoplasmic reticulum and a C-terminal portion that extends into the cytoplasm. The part of the protein inside the ER contains a domain known as an EF-hand that binds to calcium ions. This allows STIM1 to detect the calcium concentration within this storage compartment.

The segments of STIM1 in the cytoplasm are responsible for transmitting a signal once a change in calcium is detected. These cytoplasmic domains are composed of regions that can change shape and interact with other proteins. This design allows STIM1 to act like a switch, remaining in a resting state when ER calcium levels are high and becoming active when they drop.

How STIM1 Orchestrates Calcium Entry into Cells

The primary function of STIM1 is to manage a process called store-operated calcium entry (SOCE). This is a mechanism cells use to replenish their internal calcium supplies when they become depleted. When a cell uses its stored calcium, those stores must be refilled from outside the cell, which SOCE makes possible.

When the calcium concentration inside the endoplasmic reticulum drops, the EF-hand domain of STIM1 senses this change, triggering a structural rearrangement in the protein. The proteins, which exist as pairs (dimers), begin to cluster together into larger groups called oligomers. This clustering signals that the cell’s calcium stores are low.

Once oligomerized, STIM1 clusters move through the ER membrane to locations where the endoplasmic reticulum is very close to the outer plasma membrane. At these ER-plasma membrane junctions, the activated STIM1 proteins interact with another set of proteins called ORAI channels. ORAI proteins form channels in the plasma membrane designed to let calcium pass through.

The binding of STIM1’s cytoplasmic portion to the ORAI channels causes them to open, creating a conduit for calcium ions to flow into the cytoplasm. This influx serves two purposes: it generates a sustained calcium signal for cellular activities, and it allows the cell to pump calcium back into the ER to refill its stores.

The Widespread Impact of STIM1 in the Body

The STIM1-mediated calcium signaling pathway affects the function of numerous systems. In the immune system, the activation of T-cells, a type of white blood cell, depends on this process. When a T-cell recognizes a foreign invader, the signaling cascade depletes ER calcium, activating STIM1 and ORAI channels. The subsequent calcium influx is a signal for the T-cell to proliferate and mount an immune response.

In muscle tissues, STIM1 contributes to both smooth and skeletal muscle function. For smooth muscles, such as those lining blood vessels and airways, STIM1-driven calcium entry helps regulate contraction and maintain vascular tone. In skeletal muscle, STIM1 is in the sarcoplasmic reticulum (the muscle cell’s ER), where it helps modulate calcium signals for sustained muscle contraction.

Blood clotting also relies on calcium signaling involving STIM1. Platelets, the cell fragments that initiate clot formation, are activated by a rise in cytoplasmic calcium. STIM1 and ORAI channels provide the sustained calcium influx needed for platelets to change shape, aggregate at an injury site, and form a stable clot.

STIM1 is also involved in regulating the secretion of hormones and neurotransmitters. In the nervous system, STIM1-mediated calcium entry has been implicated in processes like neuronal development and the guidance of growing nerve fibers. This demonstrates how store-operated calcium entry is adapted by different cells to control a wide array of physiological activities.

When STIM1 Goes Awry: Links to Human Diseases

Defects in STIM1 function can lead to a range of human diseases. Mutations in the STIM1 gene can disrupt the protein’s ability to sense calcium or activate ORAI channels, impairing the SOCE process. This can result in conditions known as STIM1-ORAI1 pathway disorders, which have complex symptoms affecting multiple body systems.

A major consequence of faulty STIM1 function is immunodeficiency. Because T-cell activation depends on SOCE, patients with certain STIM1 mutations can have immune systems that cannot respond properly to infections. This can lead to severe combined immunodeficiency (SCID)-like syndromes. In some cases, dysregulated calcium signaling can also lead to autoimmune problems, where the immune system attacks the body’s own tissues.

Mutations in STIM1 are also a cause of certain myopathies, or diseases that affect muscle tissue. Tubular Aggregate Myopathy (TAM) is a rare muscle disorder characterized by muscle weakness and the formation of tubular aggregates within muscle fibers. These aggregates derive from the sarcoplasmic reticulum, and the disease is linked to mutations that cause STIM1 to be constantly active, leading to abnormal calcium handling and muscle damage.

Disorders of blood clotting can also arise from STIM1 defects. Stormorken syndrome is a multi-system disorder that includes myopathy and a bleeding tendency due to dysfunctional platelets. This platelet issue is a form of thrombocytopenia, where platelets are unable to activate properly, impairing the blood’s ability to clot.